Azor Information
Azor ()
Azor () Use In Pregnancy
When pregnancy is detected, discontinue Azor () as soon as possible. When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus .
Azor () indications And Usage
Azor () is indicated for the treatment of hypertension, alone or with other antihypertensive agents
Azor () may also be used as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals.
Patients with moderate or severe hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk.
Data from an 8-week, placebo-controlled, parallel-group factorial study [see ] provide estimates of the probability of reaching a blood pressure goal with Azor () compared to amlodipine or olmesartan medoxomil monotherapy. The figures below provide estimates of the likelihood of achieving the targeted systolic or diastolic blood pressure goals with Azor () 10/40 mg compared with amlodipine or olmesartan medoxomil monotherapy, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling from all available data of that treatment group. The right tail of each curve is less reliable because of small numbers of subjects with high baseline blood pressures.
The figures above provide an approximation of the likelihood of reaching a targeted blood pressure goal (e.g., Week 8 SBP
Azor () dosage And Administration
General Considerations
The side effects of olmesartan medoxomil are generally rare and apparently independent of dose. Those of amlodipine are generally dose-dependent (mostly edema).
Maximum antihypertensive effects are attained within 2 weeks after a change in dose.
Azor () may be taken with or without food.
Azor () may be administered with other antihypertensive agents.
Dosage may be increased after 2 weeks. The maximum recommended dose of Azor () is 10/40 mg.
Replacement Therapy
Azor () may be substituted for its individually titrated components.
When substituting for individual components, the dose of one or both of the components can be increased if blood pressure control has not been satisfactory.
Add-on Therapy
Azor () may be used to provide additional blood pressure lowering for patients not adequately controlled with amlodipine (or another dihydropyridine calcium channel blocker) alone or with olmesartan medoxomil (or another angiotensin receptor blocker) alone.
Initial Therapy
The usual starting dose of Azor () is 5/20 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum dose of one 10/40 mg tablet once daily as needed to control blood pressure [See ].
Initial therapy with Azor () is not recommended in patients ≥75 years old or with hepatic impairment [See and )].
Azor () dosage Forms And Strengths
Azor () tablets are formulated for oral administration in the following strength combinations:
Azor () contraindications
Azor () warnings And Precautions
Olmesartan medoxomil
During the second and third trimesters of pregnancy, these drugs have been associated with fetal injury that includes hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Azor () as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is observed, discontinue Azor () unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose (MRHD) on a mg/m basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricular, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.
Olmesartan medoxomil
Amlodipine
Amlodipine
Azor () .
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with olmesartan medoxomil and Azor () .
Amlodipine
1/2
Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in hepatically impaired patients is recommended. The lowest dose of Azor () is 5/20 mg; therefore, initial therapy with Azor () is not recommended in hepatically impaired patients [See ].
Azor ()
Amlodipine
(6.2)
Olmesartan medoxomil
Azor () drug Interactions
The pharmacokinetics of amlodipine and olmesartan medoxomil are not altered when the drugs are co-administered.
No drug interaction studies have been conducted with Azor () and other drugs, although studies have been conducted with the individual amlodipine and olmesartan medoxomil components of Azor () , as described below, and no significant drug interactions have been observed.
In vitro
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors.
No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered with digoxin or warfarin in healthy volunteers.
The bioavailability of olmesartan medoxomil was not significantly altered by the co-administration of antacids [Al(OH)/Mg(OH)].
Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not expected.
Azor () use In Specific Populations
Of the total number of subjects in the double-blind clinical study of Azor () , 20% (384/1940) were 65 years of age or older and 3% (62/1940) were 75 years or older. No overall differences in safety or effectiveness were observed between subjects 65 years of age or older and younger subjects.
Elderly patients have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients ≥75 years old is recommended. The lowest dose of Azor () is 5/20 mg; therefore, initial therapy with Azor () is not recommended in patients ≥75 years old.
There are no studies of Azor () in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with hepatic impairment. Use caution when administering Azor () to patients with severe hepatic impairment.
Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients with hepatic impairment is recommended. The lowest dose of Azor () is 5/20 mg; therefore, initial therapy with Azor () is not recommended in hepatically impaired patients.
Azor () overdosage
There is no information on overdosage with Azor () in humans.
Amlodipine.
2
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Olmesartan medoxomil.
Azor () description
Azor () provided as a tablet for oral administration, is a combination of the calcium channel blocker (CCB) amlodipine besylate and the angiotensin II receptor blocker (ARB) olmesartan medoxomil.
The amlodipine besylate component of Azor () is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is CHCINO•CHOS.
Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.
The olmesartan medoxomil component of Azor () is chemically described as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(1-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is CHNO.
The structural formula for amlodipine besylate is:
The structural formula for olmesartan medoxomil is:
Azor () contains amlodipine besylate, a white to off-white crystalline powder, and olmesartan medoxomil, a white to light yellowish-white powder or crystalline powder. The molecular weights of amlodipine besylate and olmesartan medoxomil are 567.1 and 558.59, respectively. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol.
Each tablet of Azor () also contains the following inactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The color coatings contain polyvinyl alcohol, macrogol/polyethylene glycol 3350, titanium dioxide, talc, iron oxide yellow (5/40 mg, 10/20 mg, 10/40 mg tablets), iron oxide red (10/20 mg and 10/40 mg tablets), and iron oxide black (10/20 mg tablets).
Azor () clinical Studies
An 8-week multicenter, randomized, double-blind, placebo controlled, parallel group factorial study in patients with mild to severe hypertension was conducted to determine if treatment with Azor () was associated with clinically significant reduction in blood pressure compared to the respective monotherapies. The study randomized 1940 patients equally to one of the following 12 treatment arms: placebo, monotherapy treatment with amlodipine 5 mg or 10 mg, monotherapy treatment with olmesartan medoxomil 10 mg, 20 mg, or 40 mg, or combination therapy with amlodipine/olmesartan medoxomil at doses of 5/10 mg, 5/20 mg, 5/40 mg, 10/10 mg, 10/20 mg, and 10/40 mg. Patients discontinued their prior antihypertensive treatment. The mean baseline blood pressure of the study population was 164/102 mmHg. Of the total cohort, 970 patients were treated with the combination as initial therapy.
Treatment with Azor () resulted in statistically significant greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components.
The following table presents the results for mean reduction in seated systolic and diastolic blood pressure following 8 weeks of treatment with Azor () . Placebo-adjusted reductions from baseline in blood pressure were progressively greater with increases in dose of both amlodipine and olmesartan medoxomil components of Azor () .
The antihypertensive effect of Azor () was similar in patients with and without prior antihypertensive medication use, in patients with and without diabetes, in patients ≥65 years of age and
Azor () was effective in treating black patients (usually a low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-Black patients. This effect in black patients has been seen with ACE inhibitors, angiotensin receptor blockers, and beta-blockers.
The blood pressure lowering effect was maintained throughout the 24-hour period with Azor () once daily, with trough-to-peak ratios for systolic and diastolic response between 71% and 82%.
Upon completing the 8-week, double-blind, placebo-controlled study, 1684 patients entered a 44-week open-label extension and received combination therapy with amlodipine 5 mg plus olmesartan medoxomil 40 mg. During the open-label extension, patients whose blood pressure was not adequately controlled (i.e., did not achieve a blood pressure goal of
There are no trials of Azor () demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.
Azor () how Supplied/storage And Handling
Azor () tablets contain amlodipine besylate at a dose equivalent to 5 or 10 mg amlodipine and olmesartan medoxomil in the strengths described below.
Azor () tablets are differentiated by tablet color/size and are debossed with an individual product tablet code on one side. Azor () tablets are supplied for oral administration in the following strength and package configurations:
Azor () patient Counseling Information
Physicians should instruct female patients of childbearing age about the consequences of second and third trimester exposure to drugs that act on the renin-angiotensin system and they should be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be informed to report pregnancies to their physicians as soon as possible. [See and ].
Manufactured for Daiichi Sankyo, Inc., Parsippany, New Jersey 07054 Manufactured by Daiichi Sankyo Europe GmbH, Germany
Copyright © Daiichi Sankyo, Inc. 2007. All rights reserved.
Azor ()
Azor ()
Azor ()
