2.1 General Considerations

Dose once-daily. The dosage may be increased after 2 weeks of therapy. The maximum recommended dose of Amturnide is 300/10/25 mg.

2.2 Add-on/Switch Therapy

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.

2.3 Replacement Therapy

For patients receiving aliskiren, amlodipine and HCTZ from separate tablets, substitute Amturnide containing the same component doses.

2.4 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  [see Clinical Pharmacology (12.3)].

2.5 Dosing in Specific Populations

Renal Impairment

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 [see Warnings and Precautions (5.5)].

Hepatic Impairment

In patients with severe hepatic impairment, start amlodipine at 2.5 mg per day, a dose that is not available in Amturnide [see Warnings and Precautions (5.6)].

Elderly Patients

  Patients ≥ 75 years of age should start amlodipine at 2.5 mg, which is not available with Amturnide.

5.1 Fetal/Neonatal Morbidity and Mortality

The use of drugs that act directly on the renin-angiotensin-aldosterone system during pregnancy can cause fetal and neonatal morbidity and death. No animal studies were conducted with Amturnide; however, decreased fetal birth weight was observed in animal studies with aliskiren and intrauterine deaths were observed in animal studies with amlodipine. Amturnide can cause fetal harm when administered to a pregnant woman. When pregnancy is detected, discontinue Amturnide as soon as possible. If Amturnide is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5.2 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.

5.3 Hypotension 

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.

5.4 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.

5.5 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.

5.6 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.

5.7 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.

5.8 Hypersensitivity Reactions

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.

5.9 Systemic Lupus Erythematosus

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

5.10 Lithium Interaction

Lithium generally should not be given with thiazides [see Drug Interactions (7)].

5.11 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.

5.12 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.

5.13 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 [see Drug Interactions (7)].

5.14 Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-closure 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. 

6.1 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 [see Warnings and Precautions (5.1)]
  
• Head and neck angioedema [see Warnings and Precautions (5.2)]
  
• Hypotension [see Warnings and Precautions (5.3)]

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

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

	Amturnide	Ali/amlo	Ali/HCTZ	Amlo/HCTZ
Edema peripheral	7.1%	8.0%	2.0%	4.1%
Dizziness	3.6%	2.4%	3.4%	1.7%
Headache	3.6%	3.1%	4.0%	5.1%
Nasopharyngitis	2.6%	0.7%	2.0%	3.4%

In a long-term safety trial, the safety profile was similar to that seen in the short-term controlled trial.

Aliskiren

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

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.

HCTZ

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.

Serum Electrolytes

[See Warnings and Precautions (5.11).]

6.2 Postmarketing Experience 

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.

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.1)].

The use of drugs that act directly on the renin-angiotensin-aldosterone system during the second and third trimesters of pregnancy can cause fetal and neonatal morbidity and death. In addition, first trimester use of ACE inhibitors has been associated with birth defects in retrospective data. 

Thiazides can cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

No animal studies were conducted with Amturnide; however, decreased fetal birth weight was observed in animal studies with aliskiren and intrauterine deaths were observed in animal studies with amlodipine. Amturnide can cause fetal harm when administered to a pregnant woman. When pregnancy is detected, discontinue Amturnide as soon as possible. If Amturnide is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

Human Data and Clinical Considerations

Maternal hypertension is associated with increased risks for preterm delivery, intrauterine growth restriction, placental abruption, preeclampsia, and perinatal mortality. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. Renin inhibitors (like aliskiren), angiotensin II receptor antagonists, and angiotensin converting enzyme (ACE) inhibitors exert similar effects on the renin-angiotensin-aldosterone system. Based on several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy is associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Decreased fetal renal function may result in oligohydramnios and is associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have been reported in women using these drugs, but it is not clear whether these occurrences were due to drug exposure. Limited data are conflicting about whether first trimester use of ACE inhibitors is associated with an increased risk of birth defects, but the drugs’ mechanism of action raises a theoretical concern.

When pregnancy occurs in a patient using Amturnide, discontinue Amturnide treatment as soon as possible. Inform the patient about potential risks to the fetus based on the time of gestational exposure to Amturnide (first trimester only or later). If exposure occurs beyond the first trimester, perform an ultrasound examination.

In rare cases when another antihypertensive agent cannot be used to treat the pregnant patient, use serial ultrasound examinations to assess the intraamniotic environment. Routine fetal testing with non-stress tests, biophysical profiles, or contraction stress tests may be appropriate based on gestational age and standards of care in the community. If oligohydramnios occurs in these situations, individualized decisions about continuing or discontinuing Amturnide treatment and about pregnancy management should be made by the patient and her physicians. Be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury. 

Closely observe infants exposed to Amturnide in utero for hypotension, oliguria, and hyperkalemia. If oliguria occurs, these infants may require blood pressure and renal perfusion support. Exchange transfusion or dialysis may be required to reverse hypotension or support decreased renal function.

Animal Data

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.

Aliskiren

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.

Amlodipine 

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. 

HCTZ

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.

8.3 Nursing Mothers

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.

8.4 Pediatric Use

Safety and effectiveness of Amturnide in pediatric patients have not been established.

8.5 Geriatric Use

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.    

12.1 Mechanism of Action

Amturnide

The effects of combined treatment of aliskiren, amlodipine and HCTZ arise from the actions of these three agents on different but complementary mechanisms that regulate blood pressure. Together, inhibition of the renin-angiotensin-aldosterone system (RAAS), inhibition of calcium channel-mediated vasoconstriction, and increase of sodium chloride excretion lowers blood pressure to a greater degree than the individual components.

Aliskiren

Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin-angiotensin-aldosterone system (RAAS). Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, e.g., ACE or non-ACE pathways, is not known.

All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACE inhibitors and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked, so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents.

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 suggest that amlodipine binds to both dihydropyridine and nondihydropyridine 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.

HCTZ

The mechanism of action of the antihypertensive effect of thiazides is unknown.

HCTZ 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 HCTZ 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 coadministration of agents that block the production or function of angiotensin II tends to reverse the potassium loss associated with these diuretics.

12.2 Pharmacodynamics

Aliskiren

PRA reductions in clinical trials ranged from approximately 50% to 80%, were not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known.

Amlodipine

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once-daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects of electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Amlodipine has indications other than hypertension, which can be found in the Norvasc® package insert.

HCTZ

After oral administration of HCTZ, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours.

Amturnide

In an active-controlled trial which established the clinical efficacy of Amturnide in hypertensive patients, Amturnide was associated with a 34% reduction in PRA compared to a 63% reduction with aliskiren/amlodipine, 64% reduction with aliskiren/HCTZ and a 170% elevation with amlodipine/HCTZ.

12.3 Pharmacokinetics

Absorption and Distribution

Amturnide

Following oral administration of the fixed combination of aliskiren, amlodipine, and HCTZ, peak concentrations were achieved within 1-2 hours, 6-12 hours, and 1-4 hours for aliskiren, amlodipine and HCTZ, respectively. The rate and extent of absorption of aliskiren, amlodipine, and HCTZ following administration of the fixed combination are similar to when they are administered as individual dosage forms.

When Amturnide is taken with food, mean AUC and Cmax of aliskiren are decreased by 78% and 89%, respectively. There is no impact of food on the exposures of amlodipine and HCTZ.

Aliskiren

Aliskiren is poorly absorbed (bioavailability about 2.5%) with an accumulation half life of about 24 hours. Steady state blood levels are reached in about 7-8 days. Following oral administration, peak plasma concentrations of aliskiren are reached within 1-3 hours. When taken with a high fat meal, mean AUC and Cmax of aliskiren are decreased by 71% and 85% respectively. In the clinical trials, aliskiren was administered without a fixed relation to meals.

Amlodipine

Peak plasma concentrations of amlodipine are reached 6-12 hours after an oral administration of amlodipine. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.

HCTZ

HCTZ crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Metabolism and Elimination

Aliskiren

About one-fourth of the absorbed dose appears in the urine as parent drug. How much of the absorbed dose is metabolized is unknown. Based on the in vitro studies, the major enzyme responsible for aliskiren metabolism appears to be CYP 3A4. Aliskiren does not inhibit the CYP450 isoenzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) or induce CYP 3A4.

Transporters: Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system involved in absorption and disposition of aliskiren in preclinical studies. The potential for drug interactions at the Pgp site will likely depend on the degree of inhibition of this transporter.

Drug interactions: The effect of co-administered drugs on the pharmacokinetics of aliskiren and vice versa, were studied in several single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 1 (impact of co-administered drugs on aliskiren) and Figure 2 (impact on co-administered drugs).

Warfarin: There was no clinically significant effect of a single dose of warfarin 25 mg on the pharmacokinetics of aliskiren.

Amlodipine

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism, with 10% of the parent compound and 60% of the metabolites excreted in the urine.

Elimination of amlodipine from the plasma is biphasic, with a terminal elimination half-life of about 30-50 hours. 

HCTZ

HCTZ is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated as unchanged drug within 24 hours. The elimination half-life is between 5.8 and 18.9 hours.

Special Populations

Pediatric Patients

The pharmacokinetics of Amturnide have not been investigated in patients <18 years of age.

Geriatric Patients

The pharmacokinetics of aliskiren were studied in the elderly (≥65 years). Exposure (measured by AUC) is increased in elderly patients. Adjustment of the starting dose of aliskiren is not required in these patients [see Dosage and Administration (2.5)]. 

Elderly patients have decreased clearance of amlodipine, with a resulting increase in AUC of approximately 40%-60%; therefore, a lower initial dose of amlodipine may be required [see Dosage and Administration (2.5)].

Race

With Amturnide, pharmacokinetic differences due to race have not been studied. The pharmacokinetic differences among Blacks, Caucasians, and Japanese are minimal with aliskiren therapy.

Renal Impairment

Aliskiren

The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal impairment. Rate and extent of exposure (AUC and Cmax) of aliskiren in subjects with renal impairment did not show a consistent correlation with the severity of renal impairment. Adjustment of the starting dose is not required in patients with mild to moderate renal impairment, but Amturnide is not recommended in patients with severe renal impairment [see Dosage and Administration (2.5) and Warnings and Precautions (5.5)].

Amlodipine

The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose [see Dosage and Administration (2.5)].

Hepatic Impairment

Aliskiren

The pharmacokinetics of aliskiren were not significantly affected in patients with mild-to-severe liver disease. Consequently, adjustment of the starting dose is not required in these patients [see Dosage and Administration (2.5)].

Amlodipine

Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40%-60%. A lower initial dose of amlodipine is required for patients with severe hepatic impairment [see Dosage and Administration (2.5)].

13.1 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.)

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

[See Use in Specific Populations (8.1).]