Aliskiren and Valsartan, USP Tablets

Valturna is a single tablet for oral administration of aliskiren (an orally active, nonpeptide, potent renin inhibitor) and valsartan (an orally active, nonpeptide, specific angiotensin II antagonist acting on the ATi receptor subtype).

Aliskiren

Aliskiren hemifumarate is chemically described as (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate and its structural formula is

Molecular formula: C30H53N3O6• 0.5 C4H4O4

Aliskiren hemifumarate is a white to slightly yellowish crystalline powder with a molecular weight of 609.8 (free base- 551.8). It is soluble in phosphate buffer, n-octanol, and highly soluble in water.

Valsartan

Valsartan is a white to practically white fine powder, soluble in ethanol and methanol and slightly soluble in water. Valsartan's chemical name is N-(l-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-L-valine; its structural formula is

Its empirical formula is C24H29N5O3 and its molecular weight is 435.5.

Valturna tablets are formulated for oral administration to contain aliskiren hemifumarate and valsartan, USP 150/160 mg, and 300/320 mg. The inactive ingredients for all strengths of the tablets are colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, indigotin blue lake, iron oxide black, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, titanium dioxide and hypromellose.

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].
• Head and neck angioedema [See WARNINGS AND PRECAUTIONS].
• Hypotension [See WARNINGS AND PRECAUTIONS].

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.

Valturna has been evaluated for safety in more than 1,225 patients, including over 316 patients for over 1 year. In placebo-controlled clinical trials, discontinuation of therapy because of a clinical adverse event (including uncontrolled hypertension) occurred in 1.4% of patients treated with Valturna versus 2.7% of patients given placebo.

Adverse events in placebo-controlled trials that occurred in at least 1% of patients treated with Valturna and at a higher incidence than placebo included fatigue (2.6% vs. 1.4%), nasopharyngitis (2.6% vs. 2.2%), diarrhea (1.4% vs 0.9%), upper respiratory tract infection (1.4% vs. 1.1%), urinary tract infection (1.4% vs. 0.6%), influenza (1.1% vs 0.2%), and vertigo (1.1% vs. 0.3%).

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 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, WARNINGS, and Clinical Trials].

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 vs. 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% vs. 0.3%), elevated uric acid (0.4% vs. 0.1%), gout (0.2% vs. 0.1%), and renal stones (0.2% vs. 0%).

Single episodes of tonic-clonic seizures with loss of consciousness were reported in two 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.

Valsartan has been evaluated for safety in more than 4,000 hypertensive patients in clinical trials, including over 400 treated for over 6 months, and more than 160 for over 1 year.

In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129 patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p<0.001).

Other adverse reactions, not listed above, occurring in >0.2% of patients in controlled clinical trials with valsartan are:

Body as a Whole: allergic reaction, asthenia

Musculoskeletal: muscle cramps

Neurologic and Psychiatric: paresthesia

Respiratory: sinusitis, pharyngitis

Urogenital: impotence

Other reported events seen less frequently in clinical trials were: angioedema.

Adverse reactions reported for valsartan for indications other than hypertension may be found in the prescribing information for Diovan.

Clinical Laboratory Test Abnormalities

Small mean decreases from baseline were seen in RBC count, hemoglobin and hematocrit in both monotherapies and combination therapy. These changes were small, but changes in hemoglobin were slightly more pronounced with the combination therapy (-0.26 g/dL) than with monotherapy regimens (-0.04 g/dL in aliskiren or -0.13 g/dL in valsartan) or placebo (+0.07 g/dL).

In patients without renal dysfunction, elevations in BUN (>40 mg/dL) and creatinine (>2.0 mg/dL) in any treatment group were less than 1.0%. For creatinine, 0.5% (3/599) of patients on combination treatment had a creatinine level >1.5 mg/dL at the end of the study and a 30% increase from baseline compared to none in either monotherapy or placebo [see WARNINGS].

Post-Marketing Experience

The following adverse reactions have been reported in aliskiren post-marketing experience. 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

Skin: Severe cutaneous adverse reactions, including Stevens Johnson syndrome and toxic epidermal necrolysis Peripheral edema

Included as part of the PRECAUTIONS section.

Aliskiren is an anti-hypertensive (blood pressure lowering) medication. It works by decreasing substances in the body that narrow blood vessels and raise blood pressure.

Valsartan is in a group of drugs called angiotensin II receptor antagonists. Valsartan keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.

The combination of aliskiren and valsartan is used to treat high blood pressure (hypertension).

Aliskiren and valsartan may also be used for purposes not listed in this medication guide.

Drinking alcohol can further lower your blood pressure and may increase certain side effects of aliskiren and valsartan.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Do not use salt substitutes or potassium supplements while taking aliskiren and valsartan, unless your doctor has told you to.

• Atacand
• Capozide
• Cardura
• Lopressor
• Lopressor HCT
• Lotensin

• Lotrel
• Monopril
• Tenormin IV Injection
• Toprol XL
• Zebeta

© Valturna Patient Information is supplied by Cerner Multum, Inc. and Valturna Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.