Amturnide information, interactions and side effects, Amturnide is a single tablet for oral administration of aliskiren hemifumarate (an orally active, nonpeptide, potent direct renin inhibitor), amlodipine besylate (a dihydropyridine calcium channel blocker) and HCTZ (a diuretic).
Aliskiren hemifumarate is chemically described as (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy- 2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate, and its structural formula is
Molecular formula: C30H53N3O6 • 0.5 C4H4O4
Aliskiren hemifumarate is a white to slightly yellowish powder with a molecular weight of 609.8 (free base- 551.8). It is highly soluble in water, and freely soluble in methanol, ethanol and isopropanol.
Amlodipine besylate, USP is chemically described as 3-ethyl 5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(ochlorophenyl)- 1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulfonate and its structural formula is
Molecular formula: C20H25CIN2O5•C6H6O3S
Amlodipine besylate is a white to pale yellow crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol.
HCTZ, USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. HCTZ is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.
HCTZ is a thiazide diuretic. Its empirical formula is C7H8ClN3O4S2, its molecular weight is 297.73, and its structural formula is
The inactive ingredients for all strengths of the tablets may contain colloidal silicon dioxide, crospovidone, hypromellose, iron oxide red, iron oxide yellow, iron oxide black, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide.
Amturnide is 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. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including amlodipine and hydrochlorothiazide. There are no controlled trials demonstrating risk reduction with Amturnide.
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.
DOSAGE AND ADMINISTRATION
Dose once-daily. The dosage may be increased after 2 weeks of therapy. The maximum recommended dose of Amturnide is 300/10/25 mg.
Use Amturnide for patients not adequately controlled with any two of the following: aliskiren, dihydropyridine calcium channel blockers, and thiazide diuretics.
Switch a patient who experiences dose-limiting adverse reactions attributed to an individual component—while on any dual combination of the components of Amturnide—to Amturnide at a lower dose of that component to achieve similar blood pressure reductions.
For patients receiving aliskiren, amlodipine and HCTZ from separate tablets, substitute Amturnide containing the same component doses.
Relationship to Meals
Patients should establish a routine pattern for taking Amturnide, either with or without a meal. High-fat meals decrease absorption of aliskiren substantially.
Dosing in Specific Populations
The usual regimens of Amturnide may be followed as long as the patient’s creatinine clearance is > 30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so Amturnide is not recommended.
In patients with severe hepatic impairment, start amlodipine at 2.5 mg per day, a dose that is not available in Amturnide.
Patients ≥ 75 years of age should start amlodipine at 2.5 mg, which is not available with Amturnide.
Dosage Forms And Strengths
Tablets are convex ovaloid with a beveled edge, film-coated, and unscored, in the following strengths:
||Embossing Side 1/side 2
||Pale orange brown
Storage And Handling
Tablets are convex ovaloid with a beveled edge, film-coated, and unscored, in the following strengths and packages:
|Aliskiren/ Amlodipine/ HCTZ (mg)
||Embossing Side 1/side 2
||Pale orange brown
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in original container.
Protect from heat and moisture.
Dispense in original container.
Clinical Studies Experience
The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Risk of fetal/neonatal morbidity and mortality
- Head and neck angioedema
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.
Amturnide has been evaluated for safety in 1155 patients treated with Amturnide, including 182 patients for over 1 year.
In a short-term controlled trial, there were 60.5% males, 84.1% Caucasians, 10% Blacks, 6.4% Hispanics, and 19.1% who were ≥ 65 years of age. In this study, the overall incidence of adverse events on therapy with Amturnide was similar to that observed with the individual components. The overall frequency of adverse events was similar between men and women and Black and White patients. Discontinuation of therapy because of a clinical adverse event in this study occurred in 3.6% of patients treated with Amturnide versus 2.4% in aliskiren/amlodipine, 0.7% in aliskiren/HCTZ, and 2.7% in amlodipine/HCTZ.
Table 1: Adverse events in a short-term controlled trial that occurred in at least 2% of patients treated with Amturnide
In a long-term safety trial, the safety profile was similar to that seen in the short-term controlled trial.
Aliskiren has been evaluated for safety in 6460 patients, including 1740 treated for longer than 6 months, and 1250 for longer than 1 year. In placebo-controlled clinical trials, discontinuation of therapy because of a clinical adverse event, including uncontrolled hypertension, occurred in 2.2% of patients treated with aliskiren, versus 3.5% of patients given placebo.
Two cases of angioedema with respiratory symptoms were reported with aliskiren use in the clinical studies. Two other cases of periorbital edema without respiratory symptoms were reported as possible angioedema and resulted in discontinuation. The rate of these angioedema cases in the completed studies was 0.06%.
In addition, 26 other cases of edema involving the face, hands, or whole body were reported with aliskiren use, including 4 leading to discontinuation.
In the placebo-controlled studies, however, the incidence of edema involving the face, hands, or whole body was 0.4% with aliskiren compared with 0.5% with placebo. In a long-term active-controlled study with aliskiren and HCTZ arms, the incidence of edema involving the face, hands, or whole body was 0.4% in both treatment arms.
Aliskiren produces dose-related gastrointestinal (GI) adverse reactions. Diarrhea was reported by 2.3% of patients at 300 mg, compared to 1.2% in placebo patients. In women and the elderly (age ≥ 65) increases in diarrhea rates were evident starting at a dose of 150 mg daily, with rates for these subgroups at 150 mg similar to those seen at 300 mg for men or younger patients (all rates about 2%). Other GI symptoms included abdominal pain, dyspepsia, and gastroesophageal reflux, although increased rates for abdominal pain and dyspepsia were distinguished from placebo only at 600 mg daily. Diarrhea and other GI symptoms were typically mild and rarely led to discontinuation.
Aliskiren was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any aliskiren use versus 0.6% for placebo). In active-controlled trials with ACE inhibitor (ramipril, lisinopril) arms, the rates of cough for the aliskiren arms were about one-third to one-half the rates in the ACE inhibitor arms.
Other adverse reactions with increased rates for aliskiren compared to placebo included rash (1% versus 0.3%), elevated uric acid (0.4% versus 0.1%), gout (0.2% versus 0.1%), and renal stones (0.2% versus 0%).
Single episodes of tonic-clonic seizures with loss of consciousness were reported in 2 patients treated with aliskiren in the clinical trials. One patient had predisposing causes for seizures and had a negative electroencephalogram (EEG) and cerebral imaging following the seizures; for the other patient, EEG and imaging results were not reported. Aliskiren was discontinued and there was no re-challenge in either case.
No clinically meaningful changes in vital signs or in ECG (including QTc interval) were observed in patients treated with aliskiren.
Amlodipine (Norvasc®) has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Other adverse events that have been reported at < 1% but > 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain were:
Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, postural hypotension, vasculitis
Central and Peripheral Nervous System: neuropathy peripheral, paresthesia, tremor, vertigo
Gastrointestinal: anorexia, constipation, dyspepsia,** dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia
General: allergic reaction, asthenia,** back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease
Musculoskeletal System: arthralgia, arthrosis, muscle cramps,** myalgia
Psychiatric: sexual dysfunction (male** and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization
Respiratory System: dyspnea, epistaxis
Skin and Appendages: angioedema, erythema multiforme, pruritus,** rash,** rash erythematous, rash maculopapular
**These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.
Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus
Urinary System: micturition frequency, micturition disorder, nocturia
Autonomic Nervous System: dry mouth, sweating increased
Metabolic and Nutritional: hyperglycemia, thirst
Hemopoietic: leukopenia, purpura, thrombocytopenia
Other events reported with amlodipine at a frequency of ≤ 0.1% of patients include: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.
Other adverse reactions not listed above that have been reported with HCTZ, without regard to causality, are listed below:
Body as a Whole: weakness
Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation
Hematologic: aplastic anemia, agranulocytosis, hemolytic anemia
Hypersensitivity: photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions
Metabolic: glycosuria, hyperuricemia
Musculoskeletal: muscle spasm
Nervous System/Psychiatric: restlessness
Renal: renal failure, renal dysfunction, interstitial nephritis
Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis
Special Senses: transient blurred vision, xanthopsia
Clinical Laboratory Test Abnormalities
Clinical laboratory findings for Amturnide were obtained in a controlled trial of Amturnide administered at the maximal dose of 300/10/25 mg compared to maximal doses of dual therapies, i.e., aliskiren/amlodipine 300/10 mg, aliskiren/HCTZ 300/25 mg and amlodipine/HCTZ 10/25 mg.
RBC Count, Hemoglobin and Hematocrit
Small mean changes from baseline were seen in RBC count, hemoglobin and hematocrit in patients treated with Amturnide. This effect is also seen with other agents acting on the renin angiotensin system. In aliskiren monotherapy trials these decreases led to slight increases in rates of anemia compared to placebo (0.1% for any aliskiren use, 0.3% for aliskiren 600 mg daily, versus 0% for placebo). No patients discontinued Amturnide because of anemia.
Blood Urea Nitrogen (BUN)/Creatinine
No patients treated with Amturnide had elevations in BUN > 40 mg/dL or creatinine > 2.0 mg/dL.
Liver Function Tests
Occasional elevations (greater than 150% from baseline) in ALT (SGPT) were observed in 2.7% of patients treated with Amturnide, compared with 1.7-2.7% in patients treated with the dual combinations. No patients were discontinued due to abnormal liver function tests.
Serum Uric Acid
Uric acid increase > 50% from baseline was more commonly observed in patients treated with Amturnide (4.7%) compared with the dual combinations (0.4-2.8%). Gout was less commonly observed (0.3% in Amturnide-treated patients) and renal stones were not reported.
The following adverse reactions have been identified during post-approval use of either aliskiren or amlodipine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure:
Hypersensitivity: angioedema requiring airway management and hospitalization
Aliskiren: peripheral edema, Blood creatinine increased
Amlodipine: The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
No drug interaction studies have been conducted between Amturnide and other drugs. In a phase III sub-study, there was no clinically relevant change in the exposure of aliskiren, amlodipine, and HCTZ observed with Amturnide compared to the dual combinations of aliskiren and amlodipine, amlodipine and HCTZ, and aliskiren and HCTZ. Studies with the individual aliskiren, amlodipine, and HCTZ components are described below.
Cyclosporine: Avoid co-administration of cyclosporine with aliskiren.
Itraconazole: Avoid co-administration of itraconazole with aliskiren.
In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
Cimetidine: Coadministration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Grapefruit juice: Coadministration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
Maalox® (antacid): Coadministration of the antacid Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Atorvastatin: Coadministration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Digoxin: Coadministration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Warfarin: Coadministration of amlodipine with warfarin did not change the warfarin prothrombin response time.
Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.
When administered concurrently, the following drugs may interact with thiazide diuretics.
Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required.
Other antihypertensive drugs: Additive effect or potentiation.
Cholestyramine and colestipol resins: Absorption of HCTZ is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the HCTZ and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (e.g., norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxants.
Lithium: Should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and increase the risk of lithium toxicity. Refer to the package insert for lithium before use of such preparation with Amturnide.
Nonsteroidal anti-inflammatory drugs: In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Amturnide and nonsteroidal anti-inflammatory agents are used concomitantly, observe the patient to determine if the desired effect of the diuretic is obtained.
Pregnancy Category D
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 Amturnide as soon as possible.
Head and Neck Angioedema
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with aliskiren and has necessitated hospitalization and intubation. This may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACE inhibitors or angiotensin receptor antagonists. If angioedema involves the throat, tongue, glottis or larynx, or if the patient has a history of upper respiratory surgery, airway obstruction may occur and be fatal. Patients who experience these effects, even without respiratory distress, require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Prompt administration of subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL) and measures to ensure a patent airway may be necessary.
Discontinue Amturnide immediately in patients who develop angioedema, and do not re-administer.
An excessive fall in blood pressure (hypotension) was rarely seen (0.3%) in patients with uncomplicated hypertension treated with Amturnide in a controlled trial.
In patients with an activated renin-angiotensin-aldosterone system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving renin-angiotensin-aldosterone system (RAAS) blockers. Correct these conditions prior to administration of Amturnide, or start the treatment under close medical supervision.
If an excessive fall in blood pressure occurs with Amturnide, 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.
Risk of Myocardial Infarction or Increased Angina
Rarely, initiation or change to the dose of a calcium channel blocker has resulted in the development of documented increased frequency, duration or severity of angina or acute myocardial infarction, particularly in patients with severe obstructive coronary artery disease. The mechanism of this effect has not been elucidated.
Impaired Renal Function
In patients with severe renal impairment (GFR < 30 mL/min), loop diuretics are preferred to thiazides, so Amturnide is not recommended.
Uptitrate HCTZ slowly; in patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
Patients with Hepatic Impairment
Amlodipine is extensively metabolized by the liver. In patients with severe hepatic impairment, start amlodipine at 2.5 mg per day, a dose that is not available in Amturnide.
Uptitrate HCTZ slowly; minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Patients with Heart Failure
Amturnide has not been studied in patients with heart failure.
Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitors, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction.
Hypersensitivity reactions to HCTZ may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Lithium generally should not be given with thiazides.
Serum Electrolyte Abnormalities
In a short-term controlled trial the incidence of hypertensive patients who developed hypokalemia (serum potassium < 3.5 mEq/L) was 11.0% of Amturnide-treated patients compared to 19.0% of amlodipine/HCTZ patients, 4.4% of aliskiren/HCTZ patients, and 2.1% of aliskiren/amlodipine patients; the incidence of hyperkalemia (serum potassium > 5.5 mEq/L) was 3.0% compared to 2.0% of amlodipine/HCTZ patients, 0.7% of aliskiren/HCTZ patients, and 0.7% of aliskiren/amlodipine patients. No Amturnide-treated patients discontinued due to increase or decrease of serum potassium.
Perform periodic determinations of serum electrolytes to detect possible electrolyte imbalance at appropriate intervals.
Based on experience with the use of the other substances that affect the renin-angiotensin-aldosterone system (RAAS), concomitant use of Amturnide with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that increase potassium levels may lead to increases in serum potassium.
Renal Artery Stenosis
No data are available on the use of Amturnide in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. However, in studies of ACE inhibitors in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported.
Cyclosporine or Itraconazole
When aliskiren was given with cyclosporine or itraconazole, the blood concentrations of aliskiren were significantly increased. Avoid concomitant use of Amturnide with cyclosporine or itraconazole.
Acute Myopia and Secondary Angle-Closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in transient myopia and acute angleclosure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Patient Counseling Information
See FDA-Approved Patient Labeling
Instruct patients to read the Patient Package Insert before starting Amturnide and to reread each time the prescription is renewed. Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
Female patients of childbearing age should be told about the consequences of exposure to Amturnide during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Caution patients receiving Amturnide 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, discontinue Amturnide until the physician has been consulted.
Caution all 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.
Advise patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.
Tell patients receiving Amturnide not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.
Relationship to Meals
Patient should establish a routine pattern for taking Amturnide either with or without a meal. High-fat meals decrease absorption substantially .
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with Aliskiren hemifumarate, Amlodipine besylate and HCTZ
No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of aliskiren hemifumarate, amlodipine besylate and HCTZ. However, these studies have been conducted for aliskiren hemifumarate, amlodipine besylate and HCTZ alone.
Studies with Aliskiren hemifumarate
Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic (rasH2) mouse study with aliskiren hemifumarate at oral doses of up to 1500 mg aliskiren/kg/day. Although there were no statistically significant increases in tumor incidence associated with exposure to aliskiren, mucosal epithelial hyperplasia (with or without erosion/ulceration) was observed in the lower gastrointestinal tract at doses of 750 or more mg/kg/day in both species, with a colonic adenoma identified in one rat and a cecal adenocarcinoma identified in another, rare tumors in the strain of rat studied. On a systemic exposure (AUC0-24h) basis, 1500 mg/kg/day in the rat is about 4 times and in the mouse about 1.5 times the maximum recommended human dose (300 mg aliskiren/day). Mucosal hyperplasia in the cecum or colon of rats was also observed at doses of 250 mg/kg/day (the lowest tested dose) as well as at higher doses in 4- and 13-week studies.
Aliskiren hemifumarate was devoid of genotoxic potential in the Ames reverse mutation assay with S. typhimurium and E. coli, the in vitro Chinese hamster ovary cell chromosomal aberration assay, the in vitro Chinese hamster V79 cell gene mutation test and the in vivo rat bone marrow micronucleus assay.
Fertility of male and female rats was unaffected at doses of up to aliskiren 250 mg/kg/day (8 times the maximum recommended human dose of aliskiren 300 mg/60 kg on a mg/m² basis).
Studies with Amlodipine besylate
Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m² basis, similar to the maximum recommended human dose (MRHD) of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m² basis, about two and half times the MRHD. (Calculations are based on a 60-kg patient.)
Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m² basis).
Studies with HCTZ
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of HCTZ in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). These doses in mice and rats are about 117 and 39 times, respectively, the MRHD of 25 mg/day, when based on a mg/m² basis of a 60 kg individual. The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
HCTZ was not genotoxic in vitro in the Ames mutagenicity assay of S. typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of HCTZ from 43 to 1300 mcg/mL, and in the Aspergillus Nidulans nondisjunction assay at an unspecified concentration.
HCTZ had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation. These doses of HCTZ in mice and rats represent 19 and 1.5 times, respectively, the maximum recommended human dose on a mg/m² basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)
Use In Specific Populations
Pregnancy Category D
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 Amturnide as soon as possible. These adverse outcomes are usually associated with use of drugs in the second and third trimester of pregnancy. 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. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intraamniotic environment. If oligohydramnios is observed, discontinue Amturnide, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. 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 Amturnide for hypotension, oligohuria, and hyperkalemia.
No reproductive toxicity studies have been conducted with the combination of aliskiren, amlodipine besylate and HCTZ. However, these studies have been conducted for aliskiren, amlodipine besylate and HCTZ alone.
In developmental toxicity studies, pregnant rats and rabbits received oral aliskiren hemifumarate during organogenesis at doses up to 20 and 7 times the maximum recommended human dose (MRHD) based on body surface area (mg/m²), respectively, in rats and rabbits. (Actual animal doses were up to 600 mg/kg/day in rats and up to 100 mg/kg/day in rabbits.) No teratogenicity was observed; however, fetal birth weight was decreased in rabbits at doses 3.2 times the MRHD based on body surface area (mg/m²). Aliskiren was present in placentas, amniotic fluid and fetuses of pregnant rabbits.
In developmental toxicity studies, pregnant rats and rabbits received oral amlodipine maleate during organogenesis at doses approximately 10 and 20 times the maximum recommended human dose (MRHD) based on body surface area (mg/m²), respectively, in rats and rabbits. (Actual animal doses were up to 10 mg/kg/day.) No evidence of teratogenicity or other embryofetal toxicity was observed. However, litter size was decreased approximately 50% and the number of intrauterine deaths was increased approximately 5-fold for rats receiving amlodipine maleate at doses approximately 10 times the MRHD based on body surface area (mg/m²) for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
When pregnant mice and rats were given HCTZ at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the MRHD), during their respective periods of major organogenesis, there was no evidence of fetal harm.
It is not known whether aliskiren or amlodipine is excreted in human milk, but thiazides are excreted in human milk. Both aliskiren and amlodipine are secreted in the milk of lactating rats. Because of the potential for serious adverse reactions in human milk-fed infants from Amturnide, a decision should be made whether to discontinue nursing or discontinue Amturnide, taking into account the importance of the drug to the mother.
Safety and effectiveness of Amturnide in pediatric patients have not been established.
Neonates with a history of in utero exposure to Amturnide
If oliguria or hypotension occurs, direct attention towards support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
In the short-term controlled clinical trial of Amturnide, 19% of patients treated with Amturnide were ≥ 65 years. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Limited data are available related to overdosage in humans. The most likely manifestation of overdosage would be hypotension. If symptomatic hypotension occurs, provide supportive treatment.
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/m² 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. Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized; another (120 mg) was hospitalized, underwent gastric lavage and remained normotensive; the third patient (105 mg) was hospitalized and had hypotension (90/50 mmHg), which normalized following plasma expansion. A case of accidental drug overdose has been documented in a 19-month-old male who ingested 30 mg amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion, and on subsequent observation (overnight) no sequelae were noted.
If massive overdose occurs, institute active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. If hypotension occurs, initiate cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine), 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.
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 HCTZ is removed by hemodialysis has not been established. The oral LD50 of HCTZ is greater than 10 g/kg in both mice and rats. These doses are 1946 and 3892 times, respectively, the MRHD of 25 mg/day, when based on a mg/m² basis of a 60-kg individual.
Amturnide is contraindicated in patients with anuria or hypersensitivity to sulfonamide-derived drugs like HCTZ. Hypersensitivity reactions may range from urticaria to anaphylaxis.