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)].

5.1 Fetal Toxicity

 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 [see Use in Specific Populations (8.1)].

5.2 Renal Impairment/Hyperkalemia/Hypotension when Amturnide is given in combination with ARBs or ACEI

 Amturnide is contraindicated in patients with diabetes who are receiving ARBs or ACEI because of the increased risk of renal impairment, hyperkalemia, and hypotension [see Contraindications (4) and Clinical Trials (14.2)].

 Avoid use of Amturnide with ARBs or ACEI in patients with moderate renal impairment (GFR <60 ml/min).

5.3 Head and Neck Angioedema

Aliskiren

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.

5.4 Hypotension

 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. 

 A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

5.5 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.

5.6 Impaired Renal Function

 Monitor renal function periodically in patients treated with Amturnide. Changes in renal function, including acute renal failure, can be caused by drugs that affect the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or patients receiving ARB, ACEI or non-steroidal anti-inflammatory (NSAID) therapy may be at particular risk of developing acute renal failure on Amturnide [see Contraindications (4), Warnings (5.2), Clinical Trials (14.2)]. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Amturnide.

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

Amturnide

In a short-term controlled trial the incidence of patients with hypertension not concomitantly treated with an ARB or ACEI 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.

Aliskiren

 Monitor serum potassium periodically in patients receiving aliskiren. Drugs that affect the renin-angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEI [see Contraindications (4), Warnings (5.2), and Clinical Trials (14.2)], NSAIDs, or potassium supplements or potassium sparing diuretics.

Hydrochlorothiazide

Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion.

If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations), Amturnide should be discontinued. Correction of hypokalemia and any coexisting hypomagnesaemia is recommended prior to the initiation of thiazides.

5.12 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)].

5.13 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. 

5.14 Metabolic Disturbances

 Hydrochlorothiazide

 Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

 Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.

 Hydrochlorothiazide decreases urinary calcium excretion and may cause elevation of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Amturnide.

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 (5.3)]
  
• Hypotension [see Warnings and Precautions (5.4)]

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. These data do not include information from the ALTITUDE study which evaluated the use of aliskiren in combination with ARBs or ACEI [see Contraindications (4), Warnings (5.2), and Clinical Trials (14.2)].

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%), 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

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 in patients with hypertension not concomitantly treated with an ARB or ACEI 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 with hypertension not concomitantly treated with an ARB or ACEI 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.

6.2 Postmarketing Experience 

The following adverse reactions have been identified during post-approval use of either aliskiren, amlodipine or hydrochlorothiazide. 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:

Aliskiren:

Hypersensitivity: angioedema requiring airway management and hospitalization.

Peripheral edema, severe cutaneous adverse reactions, including Stevens Johnson syndrome and toxic epidermal necrolysis.

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.

Hydrochlorothiazide:

Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hyperchloremic alkalosis, impotence, visual impairment.

Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic evaluation is necessary.

8.1 Pregnancy

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 intra-amniotic 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, oliguria, and hyperkalemia [see use in Specific Populations (8.4)].

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.

Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre eclampsia), these drugs should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications (e.g. heart disease) in pregnancy should be avoided.

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.

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.

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.

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

8.6 Renal Impairment

Safety and effectiveness of Amturnide in patients with severe renal impairment (CrCl ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60-90 mL/min) or moderate (CrCl 30-60) renal impairment.

8.7 Hepatic Impairment

Aliskiren

No dose adjustment is necessary for patients with mild-to-severe liver disease.

Hydrochlorothiazide

Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

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

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.

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.

Drug Interactions

Hydrochlorothiazide

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Skeletal muscle relaxants: Possible increased responsiveness to muscle relaxants such as curare derivatives.

Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may predispose the patient to digoxin toxicity.

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%). Following oral administration, peak plasma concentrations of aliskiren are reached within 1 to 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 of aliskiren, it was administered without requiring a fixed relation of administration 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

The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%. Peak plasma hydrochlorothiazide concentrations (Cmax) are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide.

Hydrochlorothiazide binds to albumin (40 to 70%) and distributes into erythrocytes. Following oral administration, plasma hydrochlorothiazide concentrations decline bi-exponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours.

Metabolism and Elimination

Aliskiren

The effective half-life for aliskiren is 24 hours. Steady state blood levels are reached in about 7 – 8 days. 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.

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

About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as unchanged drug.

Drug interactions:

Aliskiren

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.

Hydrochlorothiazide

Drugs that alter gastrointestinal motility: The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics.

Cholestyramine: In a dedicated drug interaction study, administration of cholestyramine 2 hours before hydrochlorothiazide resulted in a 70% reduction in exposure to hydrochlorothiazide. Further, administration of hydrochlorothiazide 2 hours before cholestyramine, resulted in 35% reduction in exposure to hydrochlorothiazide.

Antineoplastic agents (e.g. cyclophosphamide, methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Special Populations

Pediatric Patients

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

Geriatric Patients

Aliskiren

The pharmacokinetics of aliskiren were studied in the elderly (≥65 years). Exposure (measured by AUC) is increased in elderly patients.

Amlodipine

Elderly patients have decreased clearance of amlodipine, with a resulting increase in AUC of approximately 40%-60%.

Hydrochlorothiazide

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.

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 [see Use in Specific Populations (8.6)].

The pharmacokinetics of aliskiren following administration of a single oral dose of 300 mg was evaluated in patients with End Stage Renal Disease (ESRD) undergoing hemodialysis. When compared to matched healthy subjects, changes in the rate and extent of aliskiren exposure (Cmax and AUC) in ESRD patients undergoing hemodialysis was not clinically significant.

Timing of hemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, no dose adjustment is warranted in ESRD patients receiving hemodialysis.

Amlodipine

The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

Hydrochlorothiazide

In a study in individuals with impaired renal function, the mean elimination half-life of hydrochlorothiazide was doubled in individuals with mild/moderate renal impairment (30 < CLcr < 90 mL/min) and tripled in severe renal impairment (≤ 30 mL/min), compared to individuals with normal renal function (CLcr > 90 mL/min) [see Use in Specific Populations (8.6)].

Hepatic Impairment

Aliskiren

The pharmacokinetics of aliskiren were not significantly affected in patients with mild-to-severe liver disease [see Use in Specific Populations (8.7)].

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 Use in Specific Populations (8.7)].

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 was not teratogenic and 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).]

14.1 Amturnide

Amturnide

Amturnide was studied in a double-blind, active-controlled study in 1181 treated hypertensive patients, of whom 773 were classified as moderately hypertensive (SBP 160-180 mmHg) and 408 as severely hypertensive (SBP 180-200 mmHg) at baseline. The mean baseline systolic/diastolic blood pressure for all randomized patients was approximately 173/105 mmHg. A total of 61% of patients were male, 19% were 65 years or older, 84% were Caucasian, and 10% were Black. 

At study initiation, patients assigned to the dual combination treatments received lower doses of their treatment combination (aliskiren 150 mg plus amlodipine 5 mg, aliskiren 150 mg plus HCTZ 12.5 mg, or amlodipine 5 mg plus HCTZ 12.5 mg), while patients assigned to the Amturnide arm received aliskiren/HCTZ 150/12.5 mg. After 3 days, Amturnide patients were titrated to aliskiren/amlodipine/HCTZ 150/5/12.5 mg, while all other patients continued receiving their initial doses. After 4 weeks, all patients were titrated to their full target doses of aliskiren/amlodipine/HCTZ 300/10/25 mg, aliskiren/amlodipine 300/10, aliskiren/HCTZ 300/25 mg, or amlodipine/HCTZ 10/25 mg. 

Amturnide produced greater reductions in blood pressure than did any of the 3 dual combination treatments (p<0.001 for both diastolic and systolic blood pressure reductions). The reductions in systolic/diastolic blood pressure with Amturnide were 9.9/6.3 mmHg greater than with aliskiren/HCTZ, 7.2/3.6 mmHg greater than with amlodipine/HCTZ, and 6.6/2.6 mmHg greater than with aliskiren/amlodipine.

In the severe hypertensive patients, Amturnide produced greater reductions in blood pressure than each of the 3 dual combination treatments (p<0.001 for both diastolic and systolic blood pressure reductions). The reductions in systolic/diastolic blood pressure with Amturnide were 16.3/8.2 mmHg greater than with aliskiren/HCTZ, 9.6/4.8 mmHg greater than with amlodipine/HCTZ, and 11.4/4.9 mmHg greater than with aliskiren/amlodipine. 

The distribution of reductions in blood pressure on each treatment are shown in Figure 3 for diastolic blood pressure and in Figure 4 for systolic blood pressure. For example, Figure 3 shows that 50% of patients on Amturnide had more than 20.2 mmHg reduction in diastolic blood pressure compared to 18.7 mmHg on aliskiren/amlodipine combination, 12.7 mmHg on aliskiren/HCTZ combination, and 15.3 mmHg on amlodipine/HCTZ combination. Similarly, Figure 4 shows that 50% of patients on Amturnide had more than 36.3 mmHg reduction in systolic blood pressure compared to 30.8 mmHg on aliskiren/amlodipine combination, 28.3 mmHg on aliskiren/HCTZ combination, and 31.0 mmHg on amlodipine/HCTZ combination. The time course over which blood pressure effects developed is shown in Figures 5 and 6. As the trial had no placebo control, the treatment effects shown in Figures 3-6 include a placebo effect of unknown size.

The antihypertensive effect of Amturnide was similar in patients with and without diabetes, obese and non-obese patients, in patients ≥65 years of age and <65 years of age, and in women and men.

There are no trials of the Amturnide triple combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but two of the components, amlodipine and hydrochlorothiazide, have demonstrated such benefits.

14.2 Aliskiren in Patients with Diabetes treated with ARB or ACEI (ALTITUDE study)

Patients with diabetes with renal disease (defined either by the presence of albuminuria or reduced GFR) were randomized to aliskiren 300 mg daily (n=4283) or placebo (n=4296). All patients were receiving background therapy with an ARB or ACEI. The primary efficacy outcome was the time to the first event of the primary composite endpoint consisting of cardiovascular death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure, onset of end stage renal disease, renal death, and doubling of serum creatinine concentration from baseline sustained for at least one month. After a median follow up of about 27 months, the trial was terminated early for lack of efficacy. Higher risk of renal impairment, hypotension and hyperkalemia was observed in aliskiren compared to placebo treated patients, as shown in the table below.

Table 2: Incidence of selected adverse events in ALTITUDE

	Aliskiren N=4283		Placebo N=4296
	Serious Adverse Events* (%)	Adverse Events (%)	Serious Adverse Events* (%)	Adverse Events (%)
Renal impairment †	4.7	12.4	3.3	10.4
Hypotension ††	2.0	18.6	1.7	14.8
Hyperkalemia †††	1.1	36.9	0.3	27.1

†renal failure, renal failure acute, renal failure chronic, renal impairment

††dizziness, dizziness postural, hypotension, orthostatic hypotension, presyncope, syncope

††† Given the variable baseline potassium levels of patients with renal insufficiency on dual RAAS therapy, the reporting of adverse event of hyperkalemia was at the discretion of the investigator.

* A Serious Adverse Event (SAE) is defined as: an event which is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization, or is medically significant (i.e. defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes previously listed).

The risk of stroke (2.7% aliskiren vs 2.0% placebo) and death (6.9% aliskiren vs. 6.4% placebo) were also numerically higher in aliskiren treated patients.