5/20 5/40 10/20 10/40
Norvasc (Amlodipine ) (mg) 5 5 10 10
Benicar (Olmesartan medoxomil) (mg) 20 40 20 40
Amlodipine is in a group of drugs called calcium channel blockers. It works by relaxing the muscles of your heart and blood vessels.
Olmesartan is in a group of drugs called angiotensin II receptor antagonists (ARB). Olmesartan keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.
Azor is used to treat high blood pressure (hypertension). Azor is usually given after others have been tried without successful treatment of hypertension. Azor may also be used for other purposes not listed in this medication guide.
Azor™. Azor™ is a combination of two antihypertensive drugs: a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, and an angiotensin II receptor blocker, olmesartan medoxomil. The amlodipine component of Azor™ inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle, and the olmesartan medoxomil component of Azor™ blocks the vasoconstrictor effects of angiotensin II.
NORVASC: Amlodipine. Experimental data suggests that amlodipine binds to both dihydropyridine and nonhydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
BENICAR: Olmesartan medoxomil. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.
An AT2 receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.
Blockade of the angiotensin II receptor (ARB/Angioensin Receptor Blocker) inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.
NORVASC: Amlodipine. Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normals or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.
BENICAR: Olmesartan medoxomil. Olmesartan medoxomil doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of olmesartan medoxomil greater than 40 mg giving greater than 90% inhibition at 24 hours.
Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect on serum potassium.
Questions
- Indemnification: The sponsor likes to be held harmless for acts of negligence that the PI commits that are solely the error of the treating physician. For example, if a PI treats a subject's UTI during a study and the patient suffers an injury from this, it is squarely the PI’s fault and it would not be proper for the sponsor to sustain an injury by being held liable for it. However, we are aware of a BP study where the PI followed the protocol and had the subject wash off their BP medication and suffer a stroke from the lack of the proper BP treatment. The sponsor forced the PI to use his medical malpractice insurance to satisfy the claim for medical malpractice. Clearly, this was an injustice as the PI was following the protocol precisely and even though it is unusual for a stroke to occur during wash out, it certainly does not immunize the subject from having a stroke. When a stroke occurs during wash out it is important that the sponsor take responsibility for the liability. This should be true of any injury ex officio of changing a subject’s treatment while following the protocol. If this drug causes respiratory depression, are you going to be fully liable?
- Study Fully Populated Causing Premature Early Termination: As sites advertise for patients to become research volunteers, the people that are good enough to step forward to join, wash off of their existing treatment, come to our site and devote a significant amount of their time with blood draws, signing paperwork and allowing the experimental protocol to progress, should be guaranteed that the sponsor will not prematurely shut down the study because they have obtained the needed number of subjects. That is, it should be the sponsor’s responsibility to do the number crunching early enough not to allow subjects to sign consent and undergo early termination just because the study is now considered full enough. This is not ethical or in the patients best interest. All subjects who sign consent must be allowed to continue thru the protocol if they are continuing to fulfill criteria regardless of how many subjects are in the trial.
- Reimbursement for Screen Failures: Sites are taking finincial risk in the name of enrolling only those subjects who will successfully complete the trial. Sponsors need to recognize that this significantly slows enrollment. When we see a subject who may qualify but then again may not, we would be hesitant to enroll in that study. Since the exclusivity clock starts clicking as soon as the drug is patented it is imperative that the studies are done as quickly as possible. Sites that are rewarded for each piece of work they legitimately perform will have to enroll better. Sites with too high screen failure rates can be turned off to ensure the proper motivation to enroll high quality subjects is present.
- Sponsor Early Term Study: Should the Sponsor ET the study after the site has put a significant amount of work into preparing for it, what finincial arrangements are being thought of to compensate the site? After all, we found the trial, reviewed the IB, isolated potentially eligible subjects and advertised. The rest of the study is the relatively easy part. This goes along with start-up cost reimbursement. There should be a fee paid to the sites for start-up costs to help defray this potentiality. Paying more per subject to compensate for start-up costs leaves the site liable for the costs related to the sponsor unilaterally stopping the trial.
- Initial Fasting Labs and Informed Consent: Many trials have “visit one” with fasting labs and signing informed consent on the same day. This is less desirable than having a visit one where the subject presents non-fasting for the purpose of signing the informed consent form and having the study discussed with them. The potential problem is with a diabetic. If a diabetic patient answers an ad and presents fasting for visit one, a research related procedure was done prior to signing the ICF (Informed Consent Form). They could get a low sugar reaction while driving to the site and suffer an MVA. They may also feel pressured to sign the ICF quickly as they know when the do so they will finally get something to eat. This can be most safely avoided by allowing subjects to sign the ICF on a pre-visit one or by writing protocols that don't have fasting labs as a visit one procedure. Although I understand V1 labs are non-fasting for this trial.
- Recruitment: Too often recruitment is an oversight thought to be the sites problem dealt with at a time other than the beginning of the trial. It becomes the sponsor’s problem after many sites under enroll. Wise sponsors address recruitment up front at the investigator’s meeting and include recruitment agencies. One budget neutral solution is for the sponsor to push to make available an IRB approved ad for those using the central IRB at the very beginning of the trial. In addition use of centralized recruitment agencies like Pi and Acurian can very useful and cost effective. All our databases could be larger. A small minority of people step forward to become research subject volunteers. Planning for recruitment issues at the beginning is much better than catch up at the end.
Impediments to Enrollment