Parameters Candesartan Eprosartan Irbesartan Losartan Olmesartan Telmirsartan Valsartan Food effect No effect <25% No effect 10% No effect 6% 40%

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1 Statewide Pharmacy and Therapeutics 7/30/04 Formulary Class Review Angiotensin II Receptor Antagonists (AIIRAs) Candesartan (Atacand, AstraZeneca) Eprosartan (Teveten, Biovail) Irbesartan (Avapro, BMS/S-S) Losartan (Cozaar, Merck) Olmesartan (Benicar, Sankyo Pharma) Telmisartan (Micardis, Boehringer Ingelheim) Valsartan (Diovan, Novartis) INTRODUCTION 1 Hypertension affects approximately 50 million individuals in the United States and approximately 1 billion worldwide. As the population ages, the prevalence of hypertension will increase even further unless broad and effective preventive measures are implemented. For individuals years of age, each increment of 20 mmhg in systolic BP or 10 mmhg in diastolic BP doubles the risk of CVD across the entire BP range from 115/75 to 185/115 mmhg. The benefits of lowering blood pressure have been proven in multiple clinical trials. Antihypertensive therapy has been associated with reductions in stroke incidence averaging percent; myocardial infarction, percent; and heart failure, more than 50 percent. The JNC 7 guidelines recommend a goal of blood pressure less than 140/90 mm Hg. However, for those with diabetes or renal disease, a lower BP goal of less than 130/80 mm Hg is recommended. INDICATIONS 1,6 The AIIRAs are indicated for the treatment of hypertension, alone or in combination with other antihypertensive agents. Losartan (Cozaar) and irbesartan (Avapro) are indicated for neuropathy in type 2 diabetes, valsartan (Diovan) for the treatment of heart failure in patients who are intolerant of ACEIs, and losartan (Cozaar) is indicated for hypertension with left ventricular hypertrophy, but there is evidence that this benefit does not apply to black patients. The JNC 7 recommends the AIIRAs be used in heart failure, diabetes, and chronic kidney disease. In heart failure, for those with symptomatic ventricular dysfunction or end-stage heart disease, AIIRAs and aldosterone blockers are recommended along with a loop diuretic. In diabetic hypertension, ACEI or AIIRA-based treatments favorably affect the progression of diabetic neuropathy and reduce albuminuria, and the AIIRAs have been shown to reduce progression to microalbuminuria. In those with chronic kidney disease, ACEIs and AIIRAs have demonstrated favorable effects on the progression of diabetic and nondiabetic renal disease. PHARMACOLOGY 1 These agents are angiotensin II receptor (type AT1) antagonists. Angiotensin II (formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE); kininase II) is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system, and an important component in the pathophysiology of hypertension. Its effects are vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal re-absorption of sodium. AIIRAs block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues. There is also an AT2 receptor in many tissues, but is not known to be associated with cardiovascular homeostasis. AIIRAs do not inhibit ACE (kininase II, the enzyme that converts angiotensin I to Angiotensin II and degrades bradykinin), nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. AIIRAs inhibit the pressor effect of angiotensin II ( as well as angiotensin I) infusions. Removal of the negative feedback of angiotensin II causes a 2-3 fold increase in plasma rennin activity and a consequent rise in angiotensin II plasma concentration in hypertensive patients. The resulting increased plasma rennin activity and angiotensin II circulating levels are insufficient to alter the effects of AIIRAs on blood pressure. AIIRAs do not affect the response to bradykinin, whereas ACE inhibitors do increase the response. AIIRAs have very little effect on serum potassium.

2 PHARMACOKINETICS 1 Parameters Candesartan Eprosartan Irbesartan Losartan Olmesartan Telmirsartan Valsartan Food effect No effect <25% No effect 10% No effect 6% 40% (AUC/Cmax) Metabolism O-deethylation Glucuronidation CYP2C9 CYP2C9, CYP3A4 None Conjugation unknown Special Populations: Renal Impairment: No dosage adjustment is necessary for patients with renal impairment unless they are volume-depleted. Hepatic Impairment: A lower starting dose of losartan should be given in this population and use telmisartan and valsartan with caution as they are eliminated by biliary excretion. Elderly: No dosage adjustment is necessary when initiating AIIRAs in the elderly. Pregnancy: Category C (first trimester); Category D (second and third trimester) (therefore should not be used during pregnancy, and avoided in women who are likely to become pregnant) Lactation: AIIRAs were present in rat milk. It is not known if AIIRAs are excreted in human breast milk. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. Pediatrics: Safety and efficacy have not been established. CONTRAINDICATIONS 1,6 Hypersensivity to any component of these products. Pregnancy WARNINGS 1 BLACK BO: 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. When pregnancy is detected, discontinue AIIRAs as soon as possible. PRECAUTIONS 1 Potassium supplements: Tell patients receiving losartan not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. Liver function test: Occasional elevations (more than 150% in valsartan-treated patients) of liver enzymes or serum bilirubin have occurred. Minor elevations of ALT, AST, and alkaline phosphatase occurred with those taking eprosartan. Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit were observed in patients treated with AIIRAs. Serum potassium: Increases of more than 20% in serum potassium were observed in 4.4% of valsartantreated patients.

3 DRUG INTERACTIONS: See chart attached DRUG INTERACTIONS 1,2 Precipitant Object drug Object drug Description drug effect All AIIRAs Lithium May result in increased risk of lithium toxicity secondary to increased renal absorption of lithium. Cimetidine Losartan Co-admin led to an increase of ~ 18% in AUC of losartan Fluconazole Losartan Fluc may inhibit the CYP2C9 causing increased antihypertensive and adverse effects Indomethacin Losartan Hypotensive effect may be reduced Phenobarbital Losartan Co-admin led to a reduction of ~ 20% in the AUC of losartan Rifamycins Losartan Rifamycins may increase the metabolism of losartan, thereby decreasing antihypertensive effects Digoxin Candesartan Monitor due to possible fluctuations MONITORING PARAMETERS -Blood pressure -Liver function tests -BUN -Serum potassium DOSING and ADMINISTRATION 6 Drug Usual dose range in mg/day Daily frequency Cost range in $ Candesartan Eprosartan Irbesartan Losartan Olmesartan Telmisartan Valsartan PRODUCT AVALABILITY 1 Each individually or in combination with a diuretic. Candesartan/HCTZ (Atacand HCT) Eprosartan/HCTZ (Teveten/HCT) Irbesartan/HCTZ (Avalide) Telmisartan/HCTZ (Micardis/HCT) Valsartan/HCTZ (Diovan/HCT)

4 SUMMARY and CONCLUSION 6 Hypertension is a very serious problem in the United State and worldwide. The 7 th Report of the Joint Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, provides guidelines for hypertension management that include: Thiazide-type diuretics should be used in drug treatment for most patients with uncomplicated hypertension, either alone or in combined with drugs from other classes. Certain high risk conditions are compelling indications for the use of other antihypertensive drug classes (ACEIs, AIIRAs, BB, and CCB). Most patients will require two or more antihypertensive medications to achieve goal blood pressure. With these guidelines and recommendations and the importance of reaching the goal blood pressure it is imperative our patients are achieving their goal. When choosing an agent, the pharmacological activities, effectiveness, contraindications, adverse effects, drug interactions, compliance, and cost need to be taken into consideration. The current literature states a particular benefit to inhibition of the rennin-angiotensin system in patients with type 2 diabetes and overt neuropathy. They showed that AIIRA have a renoprotective effect in diabetic patients that is analogous to that observed with ACE inhibitors in type 1 diabetes. Unfortunately, because ACEI were not used in the trials, a direct comparison of the two classes of medication is impossible. There is also emerging evidence that patients with diabetic nephropathy or nondiabetic proteinuric nephropathy may benefit from combination therapy with an ACEI and an AIIRA. It should be remembered, however, that these medications also control blood pressure and proteinuria well when administered with other drugs, such as diuretics. REFERENCES 1. Drug Facts and Comparisons. Jan Collard CL. Hypertension. Medication Update. Southern Medical Journal.Nov (11): Jong P. Demers C. McKelvie RS. Lui PP. Angiotensin receptor blockers in heart failure: meat-analysis of randomized controlled trials. Journal of American College of Cardiology. Feb 6, 2003, 39(3): Keane WF. Lyle PA. Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan Study. Recent advances in management of type 2 diabetes and neuropathy: lessons from the RENAAL study. American Journal of Kidney Disease. Mar (3supp): S MICROMEDE Healthcare Series: MICROMEDE, Greenwood Village, Colorado. 6. National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Available at: 7. Slagle MA. Antihypertensive Medications. Medication Update. Southern Medical Journal.Nov (11): Thurman JM. Schrier RW. Comparative effects of angiotensin-converting enzyme inhibitors and angiotension receptor blockers on blood pressure and the kidney. American Journal of Medicine May. (7):

5 Adverse reaction Cardio CNS Dermatologic Candesartan palpations Paresthesia, vertigo, somnolence Eprosartan Irbesartan Losartan Olmesartan Telmisartan Valsartan Angina, bradycardia, abnormal ECG, a fib, hypotension Ataxia, migraine, nervousness, somnolence, tremor, vertigo Eczema, pruritus, increased sweating Flushing, hypertension, cardiac murmur, MI Sleep disturbance, paresthesia, tremor, CVA Pruritus, dermatitis Endocrine Sexual dysf, libido change, gout GI Anorexia, dry mouth Constipation, oral lesion GU Hematologic Metabolic hyperuricemia Misc Respiratory Other Comments Post marketing Asthenia, fever, dyspnea, sweating Angina, MI, angioedema AR occurred at about the same in m/f and b/nonb Abnormal hepatic function, hepatitis, neutropenia, leucopenia, agranulocytosis, purities, urticaria Cystitis, polyuria Anemia, purpura DM, gout, hypercholesterolemia, hyperkalemia, hyponatremia Alcohol intolerance, fever, hot flashes, rigors, leg cramps, facial edema asthma Abnormal urination Fever, chills, facial edema Epistaxis, congestion Hypotension and orthostatic hypotension was low Urticaria, angioedema, increased LFTs, jaundice Angina, CVA, hypotension, MI, palpitations Anxiety d/o, ataxia, confusion, dream abnor, decreased libido Alopecia, dry skin, dermatitis, photosensisivity Anorexia, constipation Impotence, nocturia Asthenia/fatigue, facial edema, fever, syncope, anemia Dyspnea, resp congestion Hepatitis, dry cough, hyperkalemia, hyponatremia, anaphylactic reactions have been reported Gastroenteritis, nausea Hypercholesterolemia, hyperlipidemia, hyperurcemia Pain, vertigo, facial edema Palpitations, leg edema, abnor ECG Somnolence, migraine vertigo Dermatitis, eczema, pruritus Flatulence, constipation, vomiting, dry mouth Micturition frequency Gout, hypercholesterolemia, DM Impotence, sweating, flushing, leg pain, otitis media Asthma, dyspnea Paresthesia, somnolence Constipation, dry mouth, flatulence Allergic reaction, asthenia, palpitations, dyspnea, vertigo Hepatitis, elevated LFT s, angioedema, impaired renal function, hyperkalemia, alopecia

6 Failure Mode Effects Analysis (FMEA) for Formulary Review Medication: Angiotensin II Receptor Antagonists Date: 7/30/04_ Potential Failure Mode Yes No 1. Are there specific medication errors or adverse events that have been associated with this drug? List: 2. Does this medication need to be administered in a particular way to be effective? (Example with or without food, timed around other meds) List: 3. Are there clinically significant drug interactions? List: Lithium, digixon/candesartan, indomethacin/losartan 4. Is this medication potentially toxic? How critical is dosing? List: volume depletion 5. Are there educational needs that should be addressed prior to addition to the formulary? List: _potassium supplementation/salt substitute/losartan 6. Does the medication look-like or sound-like other formulary products? List: 7. Do policy, procedures, or forms need to be rewritten or changed and approved before this medication should be released? List: AIIRAs should be used primarily in patients in whom ACEI are indicated, but who are unable to tolerate them

7 8. Are there any concerns that need to be addressed before this medication is added to the drug database? (Example labeling, 5 digit code, dose information, allergies) List: 9. Are there any specific monitoring parameters that should be recommended? List: _BP, LFT s, BUN, serum potassium