Aliskiren

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 Tekturna HCT as soon as possible [see Use in Specific Populations ( 8.1)].

Hydrochlorothiazide

Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possible other adverse reactions that have occurred in adults [see Use in Specific Populations ( 8.1)].

Aliskiren

Hypersensitivity reactions such as anaphylactic reactions and angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients treated with Tekturna 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 ACEIs or angiotensin receptor antagonists. Anaphylactic reactions have been reported from postmarketing experience with unknown frequency. 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 and appropriate monitoring measures since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Prompt administration of subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and measures to ensure a patent airway may be necessary.

Discontinue Tekturna HCT immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister [see Contraindications ( 4)] .

Hydrochlorothiazide (HCTZ)

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.

Hydrochlorothiazide (HCTZ)

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

Tekturna HCT

In the short-term controlled trials of various doses of Tekturna HCT, in patients with hypertension not concomitantly treated with an ARB or ACEI, the incidence of hypertensive patients who developed hypokalemia (serum potassium less than 3.5 mEq/L) was 2.2%; the incidence of hyperkalemia (serum potassium greater than 5.5 mEq/L) was 0.8%. No patients discontinued due to increase or decrease of serum potassium.

Aliskiren

Monitor serum potassium periodically in patients receiving aliskiren. Drugs that affect the RAAS can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEIs [see Contraindications ( 4), Warnings and Precautions ( 5.2), and Clinical Studies ( 14.4)], NSAIDs, including selective Cyclooxygenase-2 inhibitors (COX-2 inhibitors), or potassium supplements or potassium-sparing diuretics.

Hydrochlorothiazide (HCTZ)

HCTZ 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), Tekturna HCT should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides.

Aliskiren

When aliskiren was given with cyclosporine or itraconazole, the blood concentrations of aliskiren were significantly increased. Avoid concomitant use of aliskiren with cyclosporine or itraconazole [see Drug Interactions ( 7)] .

Hydrochlorothiazide (HCTZ)

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

HCTZ 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.

HCTZ decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Tekturna HCT.

Tekturna HCT

Tekturna HCT has been evaluated for safety in more than 2,700 patients, including over 700 treated for 6 months and 190 for over 1 year. In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event (including uncontrolled hypertension) occurred in 2.7% of patients treated with Tekturna HCT versus 3.6% of patients given placebo.

Adverse events in placebo-controlled trials that occurred in at least 1% of patients treated with Tekturna HCT and at a higher incidence than placebo included dizziness (2.3% versus 1%), influenza (2.3% versus 1.6%), diarrhea (1.6% versus 0.5%), cough (1.3% versus 0.5%), vertigo (1.2% versus 0.5%), asthenia (1.2% versus 0%), and arthralgia (1% versus 0.5%).

Aliskiren

Aliskiren has been evaluated for safety in 6,460 patients, including 1,740 treated for longer than 6 months, and 1,250 for longer than 1 year. In placebo-controlled clinical trials, discontinuation of therapy due to 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 ACEIs [see Contraindications ( 4), Warnings and Precautions ( 5.2), and Clinical Studies ( 14.4)].

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 years and older) increases in diarrhea rates were evident starting at a dose of 150 mg daily, with rates for these subgroups at 150 mg comparable to those seen at 300 mg for men or younger patients (all rates about 2% to 2.3%). 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 rechallenge in either case.

No clinically meaningful changes in vital signs or in ECG (including QTc interval) were observed in patients treated with aliskiren.

Hydrochlorothiazide (HCTZ)

Other adverse reactions 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, leukopenia, hemolytic anemia, thrombocytopenia;

Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions

Metabolic: hyperglycemia, 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

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Tekturna HCT in patients with hypertension not concomitantly treated with an ARB or ACEI.

Aliskiren

Hypersensitivity: anaphylactic reactions and angioedema requiring airway management and hospitalization, urticaria, peripheral edema, hepatic enzyme increase with clinical symptoms of hepatic dysfunction, severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, pruritus, erythema, hyponatremia , nausea, vomiting.

Hydrochlorothiazide

Acute renal failure, renal disorder, aplastic anemia, erythema mutliforme, 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.

Non-melanoma Skin Cancer: Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

Risk Summary

Tekturna HCT can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin- angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin- angiotensin system from other antihypertensive agents. When pregnancy is detected, discontinue Tekturna HCT as soon as possible.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 15-20%, respectively.

Clinical Considerations

Aliskiren

Use of drugs that act on the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, oligohydramnios, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death. 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.

In patients taking Tekturna HCT during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Tekturna HCT for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur in neonates with a history of in utero exposure to Tekturna HCT, support blood pressure and renal perfusion Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function.

Hydrochlorothiazide

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

Data

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/m 2), 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/m 2). Aliskiren was present in placentas, amniotic fluid and fetuses of pregnant rabbits.

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. HCTZ, 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 HCTZ for other indications (e.g., heart disease) in pregnancy should be avoided.

These animal studies were conducted according to the standards of the time.

Risk Summary

There is no information regarding the presence of Tekturna HCT or aliskiren in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that hydrochlorothiazide is present in human milk. However, there is insufficient information to determine the effects hydrochlorothiazide on the breastfed infant or the effects of hydrochlorothiazide on milk production. Because of the potential for serious adverse reactions, including hypotension, electrolyte imbalances and renal impairment in nursing infants, advise a nursing woman that breastfeeding is not recommended during treatment with Tekturna HCT.

Neonates with a history of in utero exposure to Tekturna HCT:

If oliguria or hypotension occurs, direct attention toward 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.

Aliskiren

No dose adjustment is necessary for patients with mild-to-severe liver disease [see Clinical Pharmacology ( 12.3)].

Hydrochlorothiazide (HCTZ)

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

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.

Hydrochlorothiazide (HCTZ)

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.

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

Tekturna HCT

In placebo-controlled clinical trials, PRA was decreased with aliskiren monotherapy (ranging from 54% to 65%) and increased with hydrochlorothiazide monotherapy (ranging from 4% to 72%). Treatment with Tekturna HCT resulted in PRA reductions ranging from approximately 46% to 63% in various doses despite the increase in PRA with hydrochlorothiazide treatment. The clinical implications of the differences in effect on PRA are not known.

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.

Hydrochlorothiazide (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 (HCTZ)

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.

Absorption and Distribution

Metabolism and Elimination

Hydrochlorothiazide (HCTZ)

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

Drug Interactions:

Aliskiren

The effect of coadministered 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 5 (impact of coadministered drugs on aliskiren) and Figure 6 (impact on coadministered drugs).

Figure 5: The Impact of Coadministered Drugs on the Pharmacokinetics of Aliskiren

*Ketoconazole: A 400 mg once daily dose was not studied, but would be expected to increase aliskiren blood levels further.

**Ramipril, valsartan, irbesartan: In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min [see Drug Interactions ( 7)].

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

Figure 6: The Impact of Aliskiren on the Pharmacokinetics of Coadministered Drugs

* Furosemide: Patients receiving furosemide may find its effects diminished after starting aliskiren. In patients with heart failure, co-administration of aliskiren (300 mg/day) reduced plasma AUC and C max of oral furosemide (60 mg/day) by 17% and 27%, respectively, and reduced 24 hour urinary furosemide excretion by 29%. This change in exposure did not result in statistically significant difference in total urine volume and urinary sodium excretion over 24 hours. However, a transient decrease in urinary sodium excretion and urine volume effects up to 12 hours were observed when furosemide was co-administered with aliskiren 300 mg/day.

**Ramipril, valsartan: In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min [see Drug Interactions ( 7)].

Hydrochlorothiazide (HCTZ)

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 HCTZ resulted in a 70% reduction in exposure to HCTZ. Further, administration of HCTZ 2 hours before cholestyramine, resulted in 35% reduction in exposure to HCTZ.

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

Tekturna HCT

No carcinogenicity, mutagenicity or fertility studies have been conducted with Tekturna HCT. However, these studies have been conducted for aliskiren as well as HCTZ alone.

Aliskiren

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 1 rat and a cecal adenocarcinoma identified in another, rare tumors in the strain of rat studied. On a systemic exposure (AUC 0-24hr) basis, 1500 mg/kg/day in the rat was about 4 times and in the mouse about 1.5 times the MRHD (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 mouse bone marrow micronucleus assay.

Fertility of male and female rats was unaffected at doses of up to 250 mg aliskiren/kg/day (8 times the MRHD of 300 mg Tekturna/60 kg on a mg/m 2 basis).

Hydrochlorothiazide (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). 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 Aspergillums 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 MRHD on a mg/m 2 basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)

Reproductive Toxicology Studies

[See Use in Specific Populations ( 8.1).]

Juvenile Animal Studies

Juvenile toxicity studies indicated increased systemic exposure to aliskiren 85- to 385-fold in 14 day and 8 day old rats respectively, compared with adult rats. The mdr1 gene expression in juvenile rats was also significantly lower when compared to adult rats. The increased aliskiren exposure in juvenile rats appears to be mainly attributed to lack of maturation of P-gp. The overexposure in juvenile rats was associated with high mortality [see Use in Specific Populations ( 8.4)] .

Valsartan

Aliskiren 150 mg and 300 mg and valsartan 160 mg and 320 mg were studied alone and in combination in an 8- week, 1,797-patient, randomized, double-blind, placebo-controlled, parallel-group, 4-arm, dose-escalation study. The dosages of aliskiren and valsartan were started at 150 mg and 160 mg, respectively, and increased at 4 weeks to 300 mg and 320 mg, respectively. Seated trough cuff blood pressure was measured at baseline, 4, and 8 weeks. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 3. In general, avoid use of aliskiren in combination with other drugs that affect the RAAS [see Contraindications ( 4), Warnings and Precautions ( 5), and Drug Interactions ( 7)] .

Amlodipine

Aliskiren 150 mg and 300 mg and amlodipine besylate 5 mg and 10 mg were studied alone and in combination in an 8- week, 1,685-patient, randomized, double-blind, placebo-controlled, multifactorial study. Treatment with aliskiren and amlodipine resulted overall in significantly greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components as shown in Table 4.

ACEIs

Aliskiren has not been studied when added to maximal doses of ACEIs to determine whether aliskiren produces additional blood pressure reduction.

There are no trials of the Tekturna HCT combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but the HCTZ component has demonstrated such benefits.