Tekturna Information
Tekturna () Warning: avoid Use In Pregnancy
Tekturna () dosage Forms And Strengths
150 mg light pink biconvex round tablet, imprinted NVR/IL (Side 1/Side 2)
300 mg light red biconvex ovaloid round tablet, imprinted NVR/IU (Side 1/Side 2)
Tekturna () contraindications
Tekturna () warnings And Precautions
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has 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 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 Tekturna () immediately in patients who develop angioedema, and do not readminister.
An excessive fall in blood pressure was rarely seen (0.1%) in patients with uncomplicated hypertension treated with Tekturna () alone in controlled trials and in
If an excessive fall in blood pressure occurs, the patient should be placed in the supine position and, if necessary, given 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.
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 [ ].
Tekturna () adverse Reactions
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.
Data described below reflect the evaluation of the safety of Tekturna () in more than 6,460 patients, including over 1,740 treated for longer than 6 months, and more than 1,250 patients 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 Tekturna () vs. 3.5% of patients given placebo.
Gastrointestinal:
Cough:
Seizures:
The following adverse events occurred in placebo-controlled clinical trials at an incidence of more than 1% of patients treated with Tekturna () , but also occurred at about the same or greater incidence in patients receiving placebo: headache, nasopharyngitis, dizziness, fatigue, upper respiratory tract infection, back pain and cough.
Other adverse effects with increased rates for Tekturna () 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%).
Aliskiren’s effect on ECG intervals was studied in a randomized, double-blind, placebo and active-controlled (moxifloxacin), 7-day repeat dosing study with Holter-monitoring and 12 lead ECGs throughout the interdosing interval. No effect of aliskiren on QT interval was seen.
Clinical Laboratory Findings
In controlled clinical trials, clinically relevant changes in standard laboratory parameters were rarely associated with the administration of Tekturna () . In multiple-dose studies in hypertensive patients, Tekturna () had no clinically important effects on total cholesterol, HDL, fasting triglycerides, fasting glucose, or uric acid.
Blood Urea Nitrogen, Creatinine
Serum Potassium
Serum Uric Acid
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
Peripheral edema
Blood creatinine increased
Tekturna () use In Specific Populations
Pregnancy Categories C (first trimester) and D (second and third trimesters) .
There is no clinical experience with the use of Tekturna () in pregnant women.
Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin-converting enzyme inhibitors. When pregnancy is detected, Tekturna () should be discontinued as soon as possible. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
In addition, first trimester use of ACE inhibitors, a specific class of drugs acting on the renin-angiotensin system, has been associated with a potential risk of birth defects in retrospective data. Healthcare professionals that prescribe drugs acting directly on the renin-angiotensin system should counsel women of childbearing potential about the potential risks of these agents during pregnancy. Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses and serial ultrasound examination should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, Tekturna () should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware; however that oligohydraminos may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in-utero exposure to a renin inhibitor should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
Tekturna () overdosage
Limited data area available related to overdosage in humans. The most likely manifestation of overdosage would be hypotension. If symptomatic hypotension occurs, supportive treatment should be initiated.
Tekturna ()
Tekturna () clinical Pharmacology
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.
Aliskiren is poorly absorbed (bioavailability about 2.5%) with an approximate accumulation half life of 24 hours. Steady state blood levels are reached in about 7-8 days.
Absorption and Distribution
Following oral administration, peak plasma concentrations of aliskiren are reached within 1 – 3 hours. When taken with a high fat meal, mean AUC and C 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.
Metabolism and Elimination
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:
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 of aliskiren on co-administered drugs).
Warfarin: There was no clinically significant effect of a single dose of warfarin 25 mg on the pharmacokinetics of aliskiren.
Special Populations
max
Race
Tekturna () Nonclinical Toxicology
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 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 (AUC) 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 and , the in vitro Chinese hamster ovary cell chromosomal aberration assay, the in vitroChinese 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 maximum recommended human dose of 300 mg Tekturna () /60 kg on a mg/m basis.)
Reproductive Toxicology Studies
2
2
2
Tekturna () clinical Studies
The antihypertensive effects of Tekturna () have been demonstrated in six randomized, double-blind, placebo-controlled 8-week clinical trials in patients with mild-to-moderate hypertension. The placebo response and placebo-subtracted changes from baseline in seated trough cuff blood pressure are shown in Table 1.
*p
†p
The studies included approximately 2,730 patients given doses of 75-600 mg of aliskiren and 1,231 patients given placebo. As shown in Table 1, there is some increase in response with administered dose in all studies, with reasonable effects seen at 150-300 mg, and no clear further increased at 600 mg. A substantial proportion (85%-90%) of the blood pressure lowering effect was observed within 2 weeks of treatment studies with ambulatory blood pressure monitoring showed reasonable control throughout the interdosing interval; the ratios of mean daytime to mean nighttime ambulatory BP range from 0.6 to 0.9.
Patients in the placebo-controlled trials continued open-label aliskiren for up to one year. A persistent blood pressure lowering effect was demonstrated by a randomized withdrawal study (patients randomized to continue drug or placebo), which showed a statistically significant difference between patients kept on aliskiren and those randomized to placebo. With cessation of treatment, blood pressure gradually returned toward baseline levels over a period of several weeks. There was no evidence of rebound hypertension after abrupt cessation of therapy.
Aliskiren lowered blood pressure in all demographic subgroups, although Black patients tended to have smaller reduction than Caucasians and Asians, as has been seen with ACE inhibitors and ARBs.
There are no studies of Tekturna () or members of the direct renin inhibitors demonstrating reductions in cardiovascular risk in patients with hypertension.
Hydrochlorothiazide
Aliskiren 75, 150, and 300 mg and hydrochlorothiazide 6.25, 12.5, and 25 mg were studied alone and in combination in an 8-week, 2,776-patient, randomized, double-blind, placebo-controlled, parallel-group, 15-arm factorial study. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 2.
Valsartan
Aliskiren 150 and 300 mg and valsartan 160 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 and 160 mg, respectively, and increased at four 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.
* The placebo change is 5.2/4.8 for week 4 endpoint which was used for the dose groups containing Aliskiren 150 mg or Valsartan 160 mg.
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.
ACE inhibitors
Aliskiren has not been studied when added to maximal doses of ACE inhibitors to determine whether aliskiren produces additional blood pressure reduction.
Tekturna () how Supplied/storage And Handling
Tekturna () is supplied as a light-pink, biconvex round tablet containing 150 mg of aliskiren, and as a light-red biconvex ovaloid tablet containing 300 mg of aliskiren. Tablets are imprinted with NVR on one side and IL, IU, on the other side of the 150, and 300 mg tablets, respectively.
All strengths are packaged in bottles and unit-dose blister packages (10 strips or 10 tablets) as described below in Table 5.
Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) [See USP Controlled Room Temperature]. Protect from moisture.
Dispense in original container.
Tekturna () patient Counseling Information
See FDA-approved patient labeling (Patient Information)
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
T2011-116
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