olmesartan medoxomil and amlodipine besylate and hydrochlorothiazide
Tablet, Film Coated · Oral
• When pregnancy is detected, discontinue olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets as soon as possible. ( 5.1 , 8.1 )
• Drugs that act directly on the renin-angiotensin system (RAS) can cause injury and death to the developing fetus. ( 5.1 , 8.1 ) WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning.
• When pregnancy is detected, discontinue olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets as soon as possible (5.1, 8.1).
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1, 8.1).
Uses
Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Limitations of Use This fixed combination drug is not indicated for the initial therapy of hypertension. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are a combination of an angiotensin II receptor blocker, a dihydropyridine calcium channel blocker, and a thiazide diuretic, indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions ( 1 ). Limitations of Use Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are not indicated for initial therapy. ( 1 )
Dosage and administration
Dose once daily. Dosage may be increased in 2 week intervals, as needed. The maximum recommended dose of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets is 40 mg/10 mg/25 mg. Dose selection should be individualized based on previous therapy.
• Dose once daily. Dosage may be increased after 2 weeks to a maximum dose of 40 mg/10 mg/25 mg once daily ( 2 ).
• Dose selection should be individualized based on previous therapy ( 2 ).
Dosage forms and strengths
Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are available in the following strength combinations: 20 mg/5 mg/12.5 mg 40 mg/5 mg/12.5 mg 40 mg/5 mg /25 mg 40 mg/10 mg/12.5 mg 40 mg/10 mg/25 mg Olmesartan medoxomil (mg) 20 40 40 40 40 Amlodipine equivalent (mg) 5 5 5 10 10 Hydrochlorothiazide (mg) 12.5 12.5 25 12.5 25 Tablets: olmesartan medoxomil/amlodipine/hydrochlorothiazide 20 mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg, and 40 mg/10 mg/25 mg ( 3 )
Contraindications
Because of the hydrochlorothiazide component, olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are contraindicated in patients with anuria, hypersensitivity to any component, or hypersensitivity to other sulfonamide-derived drugs. Do not co-administer aliskiren with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in patients with diabetes [See Drug Interactions ( 7.2 )] .
• Anuria: Hypersensitivity to sulfonamide-derived drugs ( 4 ).
• Do not co-administer aliskiren with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in patients with diabetes ( 4 ).
Warnings and precautions
• Hypotension: Correct volume or salt depletion prior to administration ( 5.2 ).
• Monitor renal function and potassium in susceptible patients
• Increased angina or myocardial infarction with calcium channel blockers may occur upon dosage initiation or increase ( 5.3 ).
• Observe for signs of fluid or electrolyte imbalance ( 5.6 ).
• Exacerbation or activation of systemic lupus erythematosus ( 5.8 ).
• Acute angle-closure glaucoma ( 5.9 ).
• Sprue-like enteropathy has been reported. Consider discontinuation of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in cases where no other etiology is found ( 5.10 ). 5.1 Fetal toxicity Olmesartan medoxomil. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets as soon as possible [see Use in Specific Populations ( 8.1 ] . Hydrochlorothiazide. Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or neonatal jaundice and thrombocytopenia [see Use in Specific Populations ( 8.1 ] . 5.2 Hypotension in Volume- or Salt-Depleted Patients Olmesartan medoxomil. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Amlodipine. Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely. 5.3 Increased Angina and/or Myocardial Infarction Amlodipine. Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction upon starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated. 5.4 Impaired Renal Function Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets Impaired renal function was reported in 2.1% of subjects receiving olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets compared to 0.2% to 1.3% of subjects receiving dual combination therapy of olmesartan medoxomil and amlodipine, olmesartan medoxomil and hydrochlorothiazide or amlodipine and hydrochlorothiazide. If progressive renal impairment becomes evident consider withholding or discontinuing olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. Olmesartan medoxomil . Changes in renal function occur in some individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets due to the olmesartan medoxomil component [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] . 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, amlodipine, and hydrochlorothiazide tablets because of the olmesartan medoxomil component. Hydrochlorothiazide. Thiazides may precipitate azotemia in patients with renal disease. Cumulative effects of the drug may develop in patients with impaired renal function. 5.5 Patients with Hepatic Impairment Amlodipine. Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2 ) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment. 5.6 Electrolyte and Metabolic Imbalances Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets contain hydrochlorothiazide which can cause hypokalemia, hyponatremia and hypomagnesmia. Hypomagnesmia can result in hypokalemia which may be difficult to treat despite potassium repletion. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets also contains olmesartan, a drug that affects the RAS. Drugs that inhibit the RAS can also cause hyperkalemia. Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.
Side effects
Most common adverse reactions (incidence ≥2%) are dizziness, peripheral edema, headache, fatigue, nasopharyngitis, muscle spasms, nausea, upper respiratory tract infection, diarrhea, urinary tract infection, and joint swelling ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 or FDA at 1-800-332-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets In the controlled trial of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets, patients were randomized to olmesartan medoxomil/amlodipine/hydrochlorothiazide 40 mg/10 mg/25 mg, olmesartan medoxomil/amlodipine 40 mg/10 mg, olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg, or amlodipine/hydrochlorothiazide 10 mg/25 mg. Subjects who received triple combination therapy were treated between two and four weeks with one of the three dual combination therapies. Safety data from this study were obtained in 574 patients with hypertension who received olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets for 8 weeks. The frequency of adverse reactions was similar between men and women, patients <65 years of age and patients ≥65 years of age, patients with and without diabetes, and Black and non-Black patients. Discontinuations because of adverse events occurred in 4% of patients treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets 40 mg/10 mg/25 mg compared to 1% of patients treated with olmesartan medoxomil/amlodipine 40 mg/10 mg, 2% of patients treated with olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg, and 2% of patients treated with amlodipine/hydrochlorothiazide 10 mg/25 mg. The most common reason for discontinuation with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets was dizziness (1%). Dizziness was one of the most frequently reported adverse reactions with incidence of 1.4% to 3.6% in subjects continuing on dual combination therapy compared to 5.8% to 8.9% in subjects who switched to olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. The other most frequent adverse reactions that occurred in at least 2% of subjects are presented in the table below: Table 1 Adverse Reaction OM 40 mg/AML 10 mg/ HCTZ 25 mg (N = 574) n (%) OM 40 mg/AML 10 mg (N = 596) n (%) OM 40 mg/HCTZ 25 mg (N = 580) n (%) AML 10 mg/ HCTZ 25 mg (N = 552) n (%) Edema peripheral 44 (7.7) 42 (7.0) 6 (1.0) 46 (8.3) Headache 37 (6.4) 42 (7.0) 38 (6.6) 33 (6.0) Fatigue 24 (4.2) 34 (5.7) 31 (5.3) 36 (6.5) Nasopharyngitis 20 (3.5) 11 (1.8) 20 (3.4) 16 (2.9) Muscle spasms 18 (3.1) 12 (2.0) 14 (2.4) 13 (2.4) Nausea 17 (3.0) 12 (2.0) 22 (3.8) 12 (2.2) Upper respiratory tract infection 16 (2.8) 26 (4.4) 18 (3.1) 14 (2.5) Diarrhea 15 (2.6) 14 (2.3) 12 (2.1) 9 (1.6) Urinary tract infection 14 (2.4) 8 (1.3) 6 (1.0) 7 (1.3) Joint swelling 12 (2.1) 17 (2.9) 2 (0.3) 16 (2.9) Syncope was reported by 1% of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets subjects compared to 0.5% or less for the other treatment groups. Olmesartan medoxomil . Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 treated for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse reactions similar to that seen with placebo. Adverse reactions were generally mild, transient, and without relationship to the dose of olmesartan medoxomil. Amlodipine . Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of the individual components of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience: Body as a Whole: asthenia, angioedema, anaphylactic reactions, peripheral edema Gastrointestinal: vomiting, diarrhea, sprue-like enteropathy [see Warnings and Precautions ( 5.10 ) ] Metabolic and Nutritional Disorders: hyperkalemia Musculoskeletal: rhabdomyolysis Urogenital System: acute renal failure, increased blood creatinine Skin and Appendages: alopecia, pruritus, urticaria Data from one controlled trial and an epidemiologic study have suggested that high-dose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18).
Drug interactions
Olmesartan medoxomil ( 7.1 ):
• Nonsteroidal anti-inflammatory drugs (NSAIDS): May lead to increased risk of renal impairment and loss of antihypertensive effect.
• Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia.
• Colesevelam hydrochloride: Consider administering olmesartan at least 4 hours before colesevelam hydrochloride dose.
• Lithium: Increases in serum lithium concentrations and lithium toxicity. Amlodipine ( 7.2 ):
• Limit simvastatin to 20 mg daily when coadministered.
• Increased exposure to cyclosporin and tacrolimus
• Increased amlodipine exposure when coadministered with CYP3A inhibitors Hydrochlorothiazide ( 7.3 ):
• Antidiabetic drugs: Dosage adjustment of antidiabetic may be required.
• Cholestyramine and colestipol: Reduced absorption of thiazides.
• NSAIDs: Can reduce the diuretic, natriuretic, and antihypertensive effects of diuretics. 7.1 Drug Interactions with Olmesartan Medoxomil 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. Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets and other agents that affect the RAS. Do not co-administer aliskiren with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in patients with diabetes [See Contraindications ( 4 )] . Avoid use of aliskiren with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in patients with renal impairment (GFR <60 ml/min). Use with Colesevelam Hydrochloride Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan. Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose [see Clinical Pharmacology ( 12.3 )] . Lithium Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of olmesartan or thiazide diuretics. Monitor lithium levels in patients receiving olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets and lithium. 7.2 Drug Interactions with Amlodipine Simvastatin Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily. [see Clinical Pharmacology ( 12.3 )]. Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology ( 12.3 )]. CYP3A Inhibitors Co-administration of amlodipine with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment. CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers. 7.3 Drug Interactions with Hydrochlorothiazide When administered concurrently the following drugs may interact with thiazide diuretics: Antidiabetic Drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required. Cholestyramine and Colestipol Resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single dose of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia. Non-steroidal Anti-inflammatory Drugs: In some patients the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when hydrochlorothiazide tablets and non-steroidal anti-inflammatory agents are used concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained.
Use in specific populations
• Lactation: Breastfeeding is not recommended ( 8.2 ).
• Renal Impairment: Avoid use in patients with creatinine clearance ≤30 mL/min ( 8.7 ) 8.1 Pregnancy Risk Summary Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death [see Clinical Considerations]. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. When pregnancy is detected, discontinue olmesartan medoxomil, amlodipine, and hydrochlorothizide tablets as soon as possible. Consider alternative antihypertensive therapy during pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Olmesartan Medoxomil Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to olmesartan for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to olmesartan, if oliguria or hypotension occur, utilize measures to maintain adequate blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and supporting renal function [see Use in Specific Populations ( 8.4 )] . Hydrochlorothiazide Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times that in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of preeclampsia, these drugs should not be used to treat hypertension in pregnant women. The use of HCTZ for other indications (e.g., heart disease) in pregnancy should be avoided. Data Animal Data No reproductive studies have been conducted with the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide. However, these studies have been conducted for olmesartan medoxomil, amlodipine and hydrochlorothiazide alone, and olmesartan medoxomil and hydrochlorothiazide together. Olmesartan Medoxomil. 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 2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m 2 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 and Hydrochlorothiazide. No teratogenic effects were observed when 1.6:1 combinations of olmesartan medoxomil and hydrochlorothiazide were administered to pregnant mice at oral doses up to 1625 mg/kg/day (122 times the MRHD on a mg/m 2 basis) or pregnant rats up to 1625 mg/kg/day (243 times the MRHD on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (0.3 times the MRHD on a mg/m 2 basis). In rats, however, fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in the dams) were significantly lower than control. The no observed effect dose for developmental toxicity in rats is 162.5 mg/kg/day, about 24 times, on a mg/m 2 basis, the MRHD of 40 mg olmesartan medoxomil/25 mg hydrochlorothiazide/day. (Calculations based on a 60 kg patient.) Amlodipine.
Pregnancy
8.1 Pregnancy Risk Summary Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death [see Clinical Considerations]. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. When pregnancy is detected, discontinue olmesartan medoxomil, amlodipine, and hydrochlorothizide tablets as soon as possible. Consider alternative antihypertensive therapy during pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Olmesartan Medoxomil Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to olmesartan for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to olmesartan, if oliguria or hypotension occur, utilize measures to maintain adequate blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and supporting renal function [see Use in Specific Populations ( 8.4 )] . Hydrochlorothiazide Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times that in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of preeclampsia, these drugs should not be used to treat hypertension in pregnant women. The use of HCTZ for other indications (e.g., heart disease) in pregnancy should be avoided. Data Animal Data No reproductive studies have been conducted with the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide. However, these studies have been conducted for olmesartan medoxomil, amlodipine and hydrochlorothiazide alone, and olmesartan medoxomil and hydrochlorothiazide together. Olmesartan Medoxomil. 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 2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m 2 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 and Hydrochlorothiazide. No teratogenic effects were observed when 1.6:1 combinations of olmesartan medoxomil and hydrochlorothiazide were administered to pregnant mice at oral doses up to 1625 mg/kg/day (122 times the MRHD on a mg/m 2 basis) or pregnant rats up to 1625 mg/kg/day (243 times the MRHD on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (0.3 times the MRHD on a mg/m 2 basis). In rats, however, fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in the dams) were significantly lower than control. The no observed effect dose for developmental toxicity in rats is 162.5 mg/kg/day, about 24 times, on a mg/m 2 basis, the MRHD of 40 mg olmesartan medoxomil/25 mg hydrochlorothiazide/day. (Calculations based on a 60 kg patient.) Amlodipine. No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m 2 basis) during their respective periods of major organogenesis (calculations based on a patient weight of 60 kg).
Pediatric use
8.4 Pediatric Use The safety and effectiveness of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in pediatric patients have not been established.
Geriatric use
8.5 Geriatric Use Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets In a controlled clinical trial, 123 hypertensive patients treated with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets were ≥65 years of age and 18 patients were ≥75 years of age. No overall differences in the efficacy or safety of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets were observed in these patient populations; however, greater sensitivity of some older individuals cannot be ruled out. The recommended initial dose of amlodipine in patients ≥ 75 years of age is 2.5 mg, a dose not available with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets.
Overdosage
There is no information on overdosage with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets in humans. Olmesartan medoxomil. Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If symptomatic hypotension should occur, supportive treatment should be initiated. The dialyzability of olmesartan is unknown. Amlodipine. Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension. 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. Hydrochlorothiazide. The most common signs and symptoms of overdose observed in humans are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD 50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, more than 1000-fold the highest recommended human dose.
Description
Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets provided as a tablet for oral administration, is a fixed combination of olmesartan medoxomil (ARB), amlodipine (CCB), and hydrochlorothiazide (thiazide diuretic). Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan medoxomil, a component of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets, is chemically described as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[ p-(o -1 H -tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is C 29 H 30 N 6 O 6 . Amlodipine besylate, a component of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets, 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 C 20 H 25 CIN 2 O 5
• C 6 H 6 O 3 S. Hydrochlorothiazide, a component of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets, is chemically described as 6-chloro-3,4-dihydro-2 H -1,2,4-benzo-thiazidiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 CIN 3 O 4 S 2 . The structural formula for olmesartan medoxomil is: The structural formula for amlodipine besylate is: The structural formula for hydrochlorothiazide is: Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide Tablets contains olmesartan medoxomil, a white to off-white crystalline powder, amlodipine besylate, a white or almost white powder, and hydrochlorothiazide, a white or practically white, crystalline powder. The molecular weights of olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide are 558.6, 567.1, and 297.7, respectively. Olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution. Each tablet of olmesartan medoxomil, amlodipine, and hydrochlorothiazide also contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch and talc. The color coating contains polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc. In addition, the 20 mg/5 mg/12.5 mg tablets contains black iron oxide, red iron oxide and yellow iron oxide; the 40 mg/10 mg/25 mg tablets and 40 mg/10 mg/12.5 mg tablets contains red iron oxide and yellow iron oxide; the 40 mg/5 mg/12.5 mg tablets and 40 mg/5 mg/25 mg tablets contain yellow iron oxide. olmesartan-medoxomil amlodipine-besylate hctz
Mechanism of action
12.1 Mechanism of Action The active ingredients of olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets target three separate mechanisms involved in blood pressure regulation. Specifically, amlodipine blocks the contractile effects of calcium on cardiac and vascular smooth muscle cells; olmesartan medoxomil blocks the vasoconstriction and sodium retaining effects of angiotensin II on cardiac, vascular smooth muscle, adrenal and renal cells; and hydrochlorothiazide directly promotes the excretion of sodium and chloride in the kidney leading to reductions in intravascular volume. For a more detailed description of the mechanisms of action for each individual component, see below. Olmesartan medoxomil. Angiotensin II is formed from angiotensin I in a reaction catalyzed by 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 AT 1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. An AT 2 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 AT 1 receptor than for the AT 2 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. Angiotensin-converting enzyme 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 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. Amlodipine. Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. 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. Hydrochlorothiazide. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is not fully understood.
How supplied
Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets contain olmesartan medoxomil, amlodipine besylate at a dose equivalent to 5 or 10 mg amlodipine, and hydrochlorothiazide in the strengths described below. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are differentiated by tablet color/size and are debossed with an individual product tablet code on one side. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are supplied for oral administration in the following strength and package configurations: Tablet Strength (OM/AML equivalent/HCTZ) Package Configuration NDC# Product Code Tablet Color and Description 20 mg/5 mg/12.5 mg Bottle of 30 Bottle of 90 70436-014-04 70436-014-06 TC 1 Peach, round shaped, biconvex, bevelled edge film coated tablet, debossed with “TC 1” one side and plain on other side. 40 mg/5 mg/12.5 mg Bottle of 30 Bottle of 90 70436-015-04 70436-015-06 TC 2 Yellow, round shaped, biconvex, bevelled edge film coated tablet, debossed with “TC 2” one side and plain on other side. 40 mg/5 mg/25 mg Bottle of 30 Bottle of 90 70436-016-04 70436-016-06 TC 3 Yellow, oval shaped, biconvex, bevelled edge film coated tablet, debossed with “TC 3” one side and plain on other side. 40 mg/10 mg/12.5 mg Bottle of 30 Bottle of 90 70436-017-04 70436-017-06 TC 4 Pink, round shaped, biconvex, bevelled edge film coated tablet, debossed with “TC 4” one side and plain on other side. 40 mg/10 mg/25 mg Bottle of 30 Bottle of 90 70436-018-04 70436-018-06 TC 5 Pink, oval shaped, biconvex, bevelled edge film coated tablet, debossed with “TC 5” one side and plain on other side. Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Patient information
Pregnancy: Tell female patients of childbearing age about the consequences of exposure to Olmesartan medoxomil, amlodipine and hydrochlorothiazide tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible. [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )]. Lactation : Advise nursing women not to breastfeed during treatment with olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets [see Use in Specific Populations ( 8.2 )] . Symptomatic Hypotension: Advise patients that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. Tell patients that if syncope occurs, olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets should be discontinued until the physician has been consulted. Tell patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. Non-melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening. Potassium Supplements: Advise patients not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider. Acute myopia and secondary angle-closure glaucoma: Advise patients to discontinue olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets and seek immediate medical attention if they experience symptoms of acute myopia or secondary angle-closure glaucoma [see Warnings and Precautions ( 5.9 )]. *All trademarks are the property of their respective owners. 10000045/01 Revised June 2025 Manufactured by: Piramal Pharma Limited, Plot No. 67-70 Sector 2, Pithampur-454775, Dist. Dhar (Madhya Pradesh), INDIA Mfg Lic. No.: 25/10/92 Distributed by: Slate Run Pharmaceuticals, LLC. Columbus, Ohio 43215 Product of India
Label text from the FDA structured product label by Slate Run Pharmaceuticals, LLC (revised Jun 30, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Olmesartan Medoxomil in 5 products
- Amlodipine Besylate in 5 products
- Hydrochlorothiazide in 5 products
olmesartan medoxomil and amlodipine besylate and hydrochlorothiazide NDC products (5)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 70436-014 | Olmesartan Medoxomil 20 mg/1; Amlodipine Besylate 5 mg/1; Hydrochlorothiazide 12.5 mg/1 Tablet, Film Coated | Slate Run Pharmaceuticals, LLC | ANDA |
| 70436-015 | Olmesartan Medoxomil 40 mg/1; Amlodipine Besylate 5 mg/1; Hydrochlorothiazide 12.5 mg/1 Tablet, Film Coated | Slate Run Pharmaceuticals, LLC | ANDA |
| 70436-016 | Olmesartan Medoxomil 40 mg/1; Amlodipine Besylate 5 mg/1; Hydrochlorothiazide 25 mg/1 Tablet, Film Coated | Slate Run Pharmaceuticals, LLC | ANDA |
| 70436-017 | Olmesartan Medoxomil 40 mg/1; Amlodipine Besylate 10 mg/1; Hydrochlorothiazide 12.5 mg/1 Tablet, Film Coated | Slate Run Pharmaceuticals, LLC | ANDA |
| 70436-018 | Olmesartan Medoxomil 40 mg/1; Amlodipine Besylate 10 mg/1; Hydrochlorothiazide 25 mg/1 Tablet, Film Coated | Slate Run Pharmaceuticals, LLC | ANDA |
Frequently asked questions
What is olmesartan medoxomil and amlodipine besylate and hydrochlorothiazide used for?
Olmesartan medoxomil, amlodipine, and hydrochlorothiazide tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from…
What are the side effects of olmesartan medoxomil and amlodipine besylate and hydrochlorothiazide?
Most common adverse reactions (incidence ≥2%) are dizziness, peripheral edema, headache, fatigue, nasopharyngitis, muscle spasms, nausea, upper respiratory tract infection, diarrhea, urinary tract infection, and joint swelling ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 or FDA at 1-800-332-1088 or www.fda.gov/medwatch. 6.1 Clinical… See the full label for the complete list.
Who makes olmesartan medoxomil and amlodipine besylate and hydrochlorothiazide?
olmesartan medoxomil and amlodipine besylate and hydrochlorothiazide is listed by 1 labeler in the FDA NDC directory, including Slate Run Pharmaceuticals, LLC.