Tablets, 150 and 300 mg Renin inhibitor Novartis Pharmaceuticals Canada Inc. 385 Bouchard blvd. Dorval, QC, H9S 1A9
* Registered trademark
Table of Contents
Pr
Rasilez *
aliskiren (as aliskiren fumarate)
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| oral | tablet 150 mg, 300 mg | For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING |
Rasilez * (aliskiren) is indicated for the treatment of mild to moderate essential hypertension. It may be used alone or concomitantly with thiazide diuretics, angiotensin converting enzyme inhibitors or dihydropyridine calcium channel blockers.
Geriatrics (> 65 years of age):
Of the total number of patients receiving Rasilez * in clinical studies, 1275 (19 %) were 65 years or older and 231 (3.4%) were 75 years or older. No differences were observed in safety and efficacy of Rasilez * in older patients compared to those under age 65.
Pediatrics (<18 years of age):
Safety and efficacy in children and adolescents have not been established. Rasilez * should not be given to this patient population.
Patients who are hypersensitive to any component of this product (see DOSAGE FORMS, COMPOSITION AND PACKAGING).
Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, Rasilez should be discontinued as soon as possible (see WARNINGS AND PRECAUTIONS: Special Populations: Pregnant Women).
Information to be Provided to the Patient
Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible
Cardiovascular
Hypotension
Symptomatic hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with Rasilez * alone. Hypotension was also infrequent during combination therapy with other antihypertensive agents (<1%). Aliskiren-induced hypotension is more likely to occur in patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (possibly as a result of treatment with a diuretic), patients on dialysis or with fluid loss through diarrhea or vomiting. This condition should be corrected prior to administration of Rasilez *, or the treatment should start under close medical supervision. If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline (see DOSAGE and ADMINISTRATION). A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. However, lower doses of Rasilez * and/or reduced concomitant diuretic therapy should be considered when symptoms re-occur.
Renal
Patients with greater than moderate renal dysfunction (creatinine >= 150 umol/L for women and >= 176.8 umol/L for men and/or eGFR < 30ml/min), a history of dialysis, nephrotic syndrome, or renovascular hypertension were excluded from clinical trials of Rasilez *. Caution should be exercised, due to the limited availability of safety information with Rasilez * in these patients, and the potential for other drugs acting on the renin-angiotensin system to increase serum creatinine and blood urea nitrogen.
No data are available on the effects of Rasilez * on renal function in patients with uni-or bilateral renal artery stenosis.
The concomitant use of aliskiren with cyclosporine, a highly potent P glycoprotein inhibitor, is not recommended (see Drug Interactions, Drug-Drug Interactions).
Gastrointestinal
In the event of severe and persistent diarrhea, Rasilez * therapy should be stopped (see CLINICAL TRIALS ADVERSE DRUG REACTIONS).
Special Populations
Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, Rasilez * 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 limb 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. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to a renin inhibitor during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Rasilez * as soon as possible. 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 examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, Rasilez * 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 oligohydramnios may not appear until after the fetus has sustained irreversible injury. There is no clinical experience with the use of Rasilez * in pregnant women. 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. Aliskiren is not removed by hemodialysis. Reproductive toxicity studies did not reveal any evidence of embryofetal toxicity or teratogenicity at oral doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. Aliskiren was present in the placenta, amniotic fluid and fetuses of pregnant rabbits. In rats, there were no adverse effects on fertility or early embryonic development or reproductive performance of the F1 generation.
It is not known whether Rasilez * is excreted in human milk. Rasilez * was excreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of Rasilez * in children and adolescents have not been established.
Of the total number of patients receiving Rasilez * in clinical studies, 1275 (19 %) were 65 years or older and 231 (3.4%) were 75 years or older. No clinically significant differences were observed in safety and efficacy of Rasilez * in older patients compared to those under age 65.
Adverse Drug Reaction Overview
Rasilez * has been evaluated for safety in more than 7,440 patients, including at least 2,580 treated for over 6 months, and at least 1,730 for over 1 year. The incidence of adverse events showed no association with gender, age, body mass index, race, or ethnicity. Treatment with Rasilez * was well tolerated with an overall incidence of adverse events similar to placebo up to 300 mg. Adverse events have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event occurred in 2.2% of patients treated with Rasilez * versus 3.5% of patients given placebo. In long-term active controlled clinical trials discontinuation of therapy due to an adverse event occurred in 5.4% of Rasilez * treated patients versus 4.7% of ramipril treated patients and 7.3% of hydrochlorothiazide treated patients.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The following adverse events occurred in the short-term, placebo controlled clinical trials in patients treated with Rasilez * at a rate of >= 1% over that of placebo-treated patients (see Table 1).
Table 1. Number (%) of patients with frequent AEs (at least 1% over placebo in any group) by preferred term - Placebo controlled, short-term studies (Pooled safety population)
| Placebo N= 781 n (%) | Ali 75mg N=478 n (%) | Ali 150mg N=774 n (%) | Ali 300mg N=768 n (%) | Ali 600mg N=296 n (%) | Ali /HCTZ N=1464 n (%) | HCTZ N=555 n (%) |
| 314 (40.2) | 193 (40.4) | 290 (37.5) | 309 (40.2) | 130 (43.9) | 591 (40.4) | 226 (40.7) |
| 45 (5.8) | 34 (7.1) | 33 (4.3) | 29 (3.8) | 5 (1.7) | 56 (3.8) | 21 (3.8) |
| 9 (1.2) | 6 (1.3) | 9 (1.2) | 18 (2.3) | 28 (9.5) | 24 (1.6) | 11 (2.0) |
| 5 (0.6) | 5 (1.0) | 6 (0.8) | 7 (0.9) | 6 (2.0) | 13 (0.9) | 6 (1.1) |
| 5 (0.6) | 5 (1.0) | 1 (0.1) | 5 (0.7) | 6 (2.0) | 12 (0.8) | 3 (0.5) |
| 5 (0.6) | 1 (0.2) | 9 (1.2) | 5 (0.7) | 2 (0.7) | 33 (2.3) | 6 (1.1) |
| 1 (0.1) | 6 (1.3) | 4 (0.5) | 4 (0.5) | 0 (0.0) | 19 (1.3) | 6(1.1) |
| 0 (0.0) | 0 (0.0) | 2 (0.3) | 3 (0.4) | 3 (1.0) | 7 (0.5) | 1 (0.2) |
| 1 (0.1) | 1 (0.2) | 3 (0.4) | 2 (0.3) | 0 (0.0) | 7 (0.5) | 5 (1.1) |
Any Adverse Event
Preferred term:
Nasopharyngitis Diarrhea
Edema peripheral Constipation Influenza Asthenia
Rash Rhinitis
Ali = aliskiren; HCTZ = hydrochlorothiazide
Note that 600 mg is double the highest recommended dose. At 600 mg o.d., diarrhea has consistently been seen across trials. The following adverse events of special interest occurred in two long-term double-blind studies (Table 2).
Table 2 Number (%) of patients with adverse events of special interest during the double-blind active controlled periods of two long-term studies.
| Aliskiren regimen # | HCTZ regimen # | Aliskiren Regimen & | Ramipril Regimen & | |
| N=566 | N=558 | N=419 | N=422 | |
| Preferred term | n (%) | n (%) | n (%) | n (%) |
| Any Adverse Event | 369 (65.2) | 343 (61.5) | 257 (61.3) | 255 (60.4) |
| Headache | 38 ( 6.7) | 53 ( 9.5) | 47 (11.2) | 35 ( 8.3) |
| Nasopharyngitis | 25 ( 4.4) | 30 ( 5.4) | 25 ( 6.0) | 26 ( 6.2) |
| Bronchitis | 16 ( 2.8) | 16 ( 2.9) | 13 ( 3.1) | 4 ( 0.9) |
| Cough | 16 ( 2.8) | 22 ( 3.9) | 17 ( 4.1) | 40 ( 9.5) |
| Back pain | 27 ( 4.8) | 25 ( 4.5) | 15 ( 3.6) | 13 ( 3.1) |
| Diarrhoea | 16 ( 2.8) | 16 ( 2.9) | 16 ( 3.8) | 7 ( 1.7) |
| Oedema peripheral | 30 ( 5.3) | 31 ( 5.6) | 16 ( 3.8) | 13 ( 3.1) |
#
In this 12-month study, the treatment regimen was aliskiren or HCTZ with forced titration and optional add-on of amlodipine.
&
In this 6-month study, the treatment regimen was aliskiren or ramipril with optional titration and optional add-on of HCTZ.
Rasilez * use was associated with a slightly increased incidence of dry cough, but less so than with angiotensin converting enzyme inhibitor use. In controlled, short-term clinical trials the incidence of cough was similar in placebo (0.6%) and Rasilez * (1.1%) patients. In a short-term active controlled trial, peripheral edema occurred in 3.4% of patients treated with amlodipine 5 mg, 11.2% of patients treated with amlodipine 10 mg, and 2.1% of patients treated with the combination of amlodipine 5 mg and aliskiren 150 mg. In other controlled short-term clinical trials, the incidence of edema was similar in placebo (0.6%) and Rasilez * treated patients (0.8% to 1.0%) except at a dose of 600 mg (2.0%). Other adverse events that occurred in short-term, controlled clinical trials of patients treated with Rasilez * (>0.5% Rasilez * patients) are listed below. It cannot be determined whether these events were causally related to Rasilez *.
Digestive:
nausea, dyspepsia, abdominal pain
Musculoskeletal:
muscle spasms, arthralgia, pain in extremity, neck pain, shoulder pain
Neurologic and Psychiatric: vertigo, insomnia Respiratory: bronchitis, pharyngolaryngeal pain, epistaxis Urinary: urinary tract infection 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 comparable to those seen at 300 mg for men or younger patients (all rates about 2.0%-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. Rare cases of colonic cancer (0.05%) were reported in the clinical trials with Rasilez *. The incidence is consistent with the expected prevalence rates of 0.1-0.3% in this patient population.
Angioedema
Angioedema, including edema of the larynx, has occurred during treatment with Rasilez *. In controlled clinical trials, angioedema occurred rarely during treatment with Rasilez * with rates comparable to treatment with placebo or hydrochlorothiazide. Patients should discontinue the treatment and should report immediately to the physician any signs suggesting allergic reactions, in particular, difficulties in breathing or swallowing, swelling of face, extremities, eyes, lips, tongue.
Abnormal Hematologic and Clinical Chemistry Findings
In short-term, controlled clinical trials, clinically relevant changes in standard laboratory parameters were rarely associated with the administration of Rasilez *. In multiple dose studies in hypertensive patients Rasilez * had no clinically important effects on total cholesterol, HDL, fasting triglycerides, fasting glucose, or uric acid. No special monitoring is necessary in patients receiving Rasilez *.
Blood Urea Nitrogen, Creatinine
Minor increases in blood urea nitrogen (BUN) were observed in less than 7% of patients with essential hypertension treated with Rasilez * alone vs. 6% on placebo. Rasilez * alone increased creatinine slightly (by ~1umol/L), but this effect increased (to 2.4umol/L) with co-administration of HCTZ. In an active controlled, double-blind 1-year clinical trial, 13.4% of Rasilez *-treated patients compared to 15.8% of hydrochlorothiazide-treated patients experienced >50% increases in blood urea nitrogen (BUN). In another active controlled, double-blind trial, >50% increases in BUN occurred in 15.5% of Rasilez *-treated patients and 16.0% of ramipril-treated patients. Increases in serum creatinine (>50%) were less frequent, occurring in 2.7% of Rasilez *-treated patients in the one-year study compared to 1.1% of patients treated with hydrochlorothiazide, and 1.7% of Rasilez *-treated patients and 1.4% of ramipril-treated patients in the other trial.
Hemoglobin and Hematocrit
Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.8 g/L and 0.16 volume percent, respectively) were observed with Rasilez * monotherapy. These decreases led to slight increases in the rate of anemia with aliskiren: 0.1% for any aliskiren use, 0.3% for aliskiren 600 mg o.d., vs. 0% for placebo). No patients discontinued therapy due to anemia. This effect is also seen with other agents acting on the renin-angiotensin system, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers, and may be mediated by reduction of angiotensin II which stimulates erythropoietin production via the AT1 receptor.
Serum Potassium
In short-term placebo controlled clinical trials, increases in serum potassium were minor and infrequent in patients with essential hypertension treated with Rasilez * alone (0.9% patients had serum potassium levels >5.5 mmol/L compared to 0.6% with placebo). However, when used in combination with an angiotensin converting enzyme inhibitor in a diabetic population, increases in serum potassium were more frequent (5.5%). Routine monitoring of electrolytes and renal function is indicated in this population. In an active controlled, double-blind, 1-year clinical trial in patients with essential hypertension, increases in serum potassium ( > 5.5 mmol/L) occurred in 36/550 (6.5%) of patients on Rasilez * compared to 20/535 (3.7%) on hydrochlorothiazide and decreases in serum potassium (< 3.5 mmol/L) occurred in 5/550 (0.9%) patients on Rasilez * compared to 96/535 (17.9%) on hydrochlorothiazide. In another active controlled, double-blind trial, increases in serum potassium (> 5.5 mmol/L) occurred in 8/412 (1.9%) of Rasilez *-treated patients compared to 4/417 (1.0%) on ramipril and decreases in potassium (< 3.5 mmol/L) occurred in 22/412 (5.3%) on Rasilez * compared to 19/417 (4.6%) on ramipril.
Creatine Kinase
In the short-term, placebo-controlled clinical trials, increases in creatine kinase of >300% were found in 22 of the 2233 (~1%) patients on aliskiren monotherapy vs. in 4/746 (0.5%) of patients on placebo. The effect, suggesting to be dose-related, seemed more common in men, and at ages <65 years. No cases were associated with renal dysfunction. In an active controlled, double-blind, 1-year clinical trial, 21 of 543 patients (3.9%) on an aliskiren regimen and 9/535 patients (1.7%) on an HCTZ regimen had > 300% increases in creatine kinase. This increase was seen more often in men than in women. In another long term study almost no elevations in CKs were seen in patients (0.5%) on an aliskiren regimen vs. in 1.3% of the patients on a ramipril regimen
Overview
Aliskiren has low potential for drug interactions. Aliskiren is mainly excreted as unchanged drug within the feces and is minimally metabolized in man. Only 1.4% of the total dose is metabolized by the enzyme CYP3A4 of the cytochrome P450 system. Rasilez * is poorly absorbed (bioavailability ~2.6% of an oral dose). Metabolism accounted for up to 20% of the absorbed dose in the systemic circulation. A quarter of the absorbed fraction in the systemic circulation is excreted unchanged in the urine. In-vitro studies have shown that Aliskiren does not inhibit the CYP450 isoenzymes (CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and CYP3A) or induce CYP3A4. As CYP3A4 is the major enzyme responsible for metabolism of aliskiren, complete inhibition may be expected to result in increased plasma levels of aliskiren (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Drug-Drug Interactions
Co-administration of aliskiren with amlodipine, digoxin, furosemide, hydrochlorothiazide, metformin, ramipril and valsartan did not result in clinically significant changes in aliskiren exposure. Co-administration with irbesartan reduced aliskiren Cmax up to 50% after multiple dosing with little effect on AUC (up to a 20% decrease).
Co-administration of aliskiren did not affect the steady-state pharmacokinetics of amlodipine, digoxin, hydrochlorothiazide, metformin, ramipril, ramiprilat or valsartan. Co-administration of aliskiren with furosemide resulted in reductions of furosemide Cmax and AUC of 49% and 28%, respectively.
Potential mechanisms of drug-drug interaction
Based on in-vitro studies, aliskiren is metabolised by the CYP3A4 enzyme system. However, pharmacokinetic studies in human volunteers seem to indicate that metabolism does not play a clinically significant role in the elimination of aliskiren. MDR1/Mdr1a/1b (Pgp) was found to be 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. Pgp substrates or weak-moderate inhibitors: No relevant interactions with atenolol, digoxin, amlodipine, and cimetidine have been observed. Pgp potent inhibitors: When administered with atorvastatin (80 mg), steady-state aliskiren (300 mg) AUC and Cmax increased by 50%. Co-administration of ketoconazole (200 mg b.i.d.) with aliskiren (300 mg) resulted in a 80% increase in plasma levels of aliskiren (AUC and Cmax). Preclinical studies indicate that aliskiren and ketoconazole co-administration enhances aliskiren gastrointestinal absorption and decreases biliary excretion. The change in plasma levels of aliskiren in the presence of atorvastatin or ketoconazole is expected to be within the range that would be achieved if the dose of aliskiren were doubled; aliskiren doses of up to 600 mg, or twice the highest recommended therapeutic dose, have been found to be well tolerated in controlled clinical trials. As a result no dose adjustment for aliskiren is necessary.
A single dose drug interaction study in healthy subjects has shown that cyclosporine (200 and 600 mg) increases Cmax of aliskiren 75 mg by approximately
2.5 fold and the AUC by approximately 5 fold. Therefore, the concomitant use of both drugs is not recommended (see Warnings and Precautions, Concomitant use of cyclosporine A).
Potassium and potassium sparing diuretics: Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of aliskiren with the following medicines may lead to increases in serum potassium: Potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium. If comedication is considered necessary, caution is advisable.
Drug-Food Interactions
When taken with food, mean AUC and Cmax of aliskiren were decreased by 71% and 85%, respectively (see DOSAGE AND ADMINISTRATION). There was a delay in median tmax by 1 h.
Drug-Herb Interactions
The interaction of aliskiren with herbal medications or supplements has not been studied.
Drug-Lifestyle Interactions
There are no physical restrictions for patients who receive aliskiren.
Recommended Dose and Dosage Adjustment
The usual recommended starting dose of Rasilez * is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 300 mg. Rasilez * may be used over a dosage range of 150 mg to 300 mg administered once daily. The antihypertensive effect is substantially present (85%-90%) within 2 weeks after initiating therapy with 150 mg per day with the maximum effect reached after 4 weeks. Rasilez * may be administered alone or concomitantly with thiazide diuretics or angiotensin converting enzyme inhibitors. Co-administration of 150 mg aliskiren and 5 mg amlodipine has been shown to be safe and effective; higher doses and other calcium channel blockers have not been tested. Rasilez * may be administered with or without food, although a high fat meal decreases drug absorption significantly. Patients should establish a convenient daily schedule of drug-intake and maintain a steady temporal relationship with food intake. No initial dosage adjustment is required for elderly patients, for patients with mild-to-severe renal impairment, or for patients with mild to severe hepatic impairment. Care should be exercised when dosing Rasilez * in patients with severe renal impairment as clinical experience is limited.
Missed Dose
If one or several doses of Rasilez * are missed, patients should be advised to take the dose as soon as they remember. If it is almost time for the next dose, patients should skip the missed dose and go back to their regular schedule. Patients should not increase the dose of Rasilez * to compensate for the missed dose(s).
Limited data are available related to overdosage in humans. The most likely manifestation of overdosage would be hypotension. If symptomatic hypotension should occur, supportive treatment should be initiated.
Mechanism of Action
Aliskiren has a novel mechanism of action which differs in pharmacologic action from the angiotensin converting enzyme inhibitors, angiotensin receptor blockers, aldosterone blockers, beta blockers, alpha blockers, diuretics and calcium channel blockers. Aliskiren is an orally active, nonpeptide, highly specific and potent direct renin inhibitor. Aliskiren targets the renin angiotensin system (RAS) at its point of activation by binding to the renin enzyme, thereby blocking the conversion of angiotensinogen to angiotensin I (Ang I). Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. This response initiates a cycle that includes the renin angiotensin system (RAS) and a homeostatic feedback loop. 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. Chronic increases in Ang II result in the expression of markers and mediators of inflammation and fibrosis that are associated with end organ damage. Aliskiren is a direct renin inhibitor that inhibits the production of Ang I, Ang II by acting at the point of activation of the renin cycle, inhibiting the conversion of angiotensinogen to Ang I and Ang II. This action suppresses the entire system, resulting in a reduction in plasma renin activity (PRA), Ang I, Ang II and aldosterone. All agents that inhibit the RAS system suppress the negative feedback loop and lead to a compensatory rise in plasma renin concentration. When this rise occurs, it is accompanied by increased levels of PRA. However, treatment with aliskiren neutralizes the feedback loop effects. As a result, despite an elevation of the plasma renin concentration, PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents.
Pharmacodynamics
Treatment with aliskiren decreases plasma renin activity (PRA) and increases plasma renin concentration (PRC) in hypertensive patients. In clinical trials, PRA reductions ranged from approximately 50%-80%. PRA reductions occurred with aliskiren monotherapy or when aliskiren was combined with other antihypertensive drugs. There was no rebound increase in PRA or blood pressure either acutely or over a 4-week period after aliskiren discontinuation. There was a weak correlation between the magnitudes of PRC elevation and blood pressure reduction.
In hypertensive patients, once-daily administration of Rasilez * at doses of 150 mg and 300 mg provided dose-dependent reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour dose interval (maintaining benefit in the early morning) with a mean trough to peak ratio for diastolic response of up to 98% for the 300 mg dose.
The potential of aliskiren to affect cardiac conduction and repolarisation was studied in a randomized, double-blind, placebo and active-controlled (moxifloxacin), repeat dosing, parallel group study, conducted for 7 days in 283 subjects. Twelve lead Holter ECGs were monitored over the entire dosing interval. No effect of aliskiren on the QT interval was seen.
Absorption: Following oral administration, peak plasma concentrations of aliskiren are reached within1-3 hours. The approximate bioavailability of aliskiren is 2.6%. Peak plasma concentrations (Cmax) and exposure (AUC) are expected to increase 2.6-fold and 2.4-fold when doubling the dose of aliskiren. When taken with food with a high fat content, mean AUC and Cmax of aliskiren are decreased by 71% and 85%, respectively, and t max is delayed by 1 h. Steady state plasma concentrations are reached within 5 to 7 days after starting once daily administration, and steady state levels are approximately 2-fold greater than following a single dose.
Aliskiren is evenly distributed systemically after oral administration. Following intravenous administration, mean volume of distribution at steady state is approximately 135 L indicating that aliskiren distributes extensively into extravascular space. Aliskiren plasma protein binding is moderate (47%-51%) and concentration independent.
Aliskiren is mainly eliminated as unchanged drug within feces. How much of the absorbed dose is metabolized is unknown. The enzyme responsible for this metabolism is CYP3A4 (see DRUG INTERACTIONS, Ketoconazole).
Approximately 0.6% of the dose is recovered in urine following oral administration. Following intravenous administration, the mean plasma clearance is approximately 9 L/h. The mean elimination half-life is about 40 hours (range 34-41 hours).
Special Populations and Conditions
The pharmacokinetics of aliskiren have not been investigated in patients < 18 years of age.
Geriatrics: The pharmacokinetics of aliskiren were studied in the elderly (>= 65 years). The exposure (measured by AUC) and Cmax of aliskiren is increased in elderly by 57% and 28%, respectively. Adjustment of the starting dose is not required in these patients (see DOSAGE AND ADMINISTRATION).
Males have slightly lower AUC (24%) than females. This difference is not clinically significant.
The pharmacokinetics of aliskiren do not differ significantly among different races and ethnicities (Blacks, Caucasians, Hispanics, and Japanese).
The pharmacokinetics of aliskiren were similar between type 2 diabetics and healthy volunteers.
The pharmacokinetics of aliskiren were not significantly affected in patients with mild-to- severe liver disease. Consequently, adjustment of the starting dose is not required in these patients (see DOSAGE AND ADMINISTRATION).
Renal Insufficiency: The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal insufficiency. Relative AUC and Cmax of aliskiren in subjects with renal impairment ranged between 0.8- to 2-fold those observed in healthy subjects following single dose administration and at steady state. These observed changes, however, did not correlate with the severity of renal impairment. Consequently, adjustment of the starting dose is not required in patients with mild-to-severe renal impairment (see DOSAGE AND ADMINISTRATION).
Do not store above 30oC. Protect from moisture.
Rasilez * is available for oral administration as film-coated tablets containing 150 mg, and 300 mg of aliskiren and the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, iron oxide colorants, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide. Rasilez * 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 blister packages (4 strips of 7 tablets).
PART II: SCIENTIFIC INFORMATION
Aliskiren fumarate
Chemical name Bis (2S, 4S, 5S, 7S) - 5 amino-N-(3-amino-2,2-dimethyl-3- oxopropyl)-4-hydroxy-7-[4-methoxy-3-(3-methoxypropoxy) benzyl]-8-methyl-2-(1-methylethyl)nonanamide] (2E)-but-2- enedionate Molecular formula: (C30H53N3O6)2 y C4H4O4
1219.6
OH H2N
O O
O
H
N NH2
O O
COOH
Aliskiren is a white to slightly yellowish crystalline powder. It is soluble in phosphate buffer, n-Octanol, and highly soluble in water.
The antihypertensive effects of Rasilez * (aliskiren) have been demonstrated in five 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 3.
Aliskiren daily dose, mg
| Study | Placebo | 75 | 150 | 300 | 600 |
| Mean change | Placebo- | Placebo- | Placebo- | Placebo- |
subtracted subtracted subtracted subtracted
| 1201 | 2.9/3.3 | 5.7/4 a | 5.9/4.5 a | 11.2/7.5 a | -- |
| 2201 | 5.3/6.3 | -- | 6.1/2.9 a | 10.5/5.4 a | 10.4/5.2 a |
| 2203 | 10/8.6 | 2.2/1.7 | 2.1/1.7 | 5.1/3.7 a | -- |
| 2204 | 7.5/6.9 | 1.9/1.8 | 4.8/2 a | 8.3/3.3 a | -- |
| 2308 | 3.8/4.9 | -- | 9.3/5.4 a | 10.9/6.2 a | 12.1/7.6 a |
a
p<0.05 vs. placebo by ANCOVA with Dunnett's procedure for multiple comparisons.
The studies included approximately 2,316 patients given doses of 75-600 mg of aliskiren and 781 patients given placebo. As shown in Table 3, there is some increase in response with administered dose in all studies, with reasonable effects seen at 150-300 mg, and no clear further increase 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 ranged 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 continued 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 reductions than Caucasians and Asians, as has been seen with ACE inhibitors and ARBs.
Diuretics
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 4.
Hydrochlorothiazide, mg
0 6.25 12.5 25
| Aliskiren, | mean | Placebo- | Placebo- | Placebo- | Placebo- |
| mg | change | subtracted | subtracted | subtracted | subtracted |
| 0 | 7.5/6.9 | -- | 3.5 p /2.1 p | 6.4 p /3.2 p | 6.8 p /2.4 p |
| 75 150 | -- -- | 1.9 /1.8 p 4.8 p /2 p | 6.8 p ha /3.8 p ha 7.8 p ha /3.4 p | 8.2 p a /4.2 pa 10.1 pha /5 pha | 9.8 p ha /4.5 p ha 12 pha / 5.7 pha |
300 -- 8.3 p /3.3 p -- 12.3 pha /7 pha 13.7 pha /7.3 pha
p = statistically significant vs. placebo (p <0.05)
h = statistically significant vs. component monotherapy HCTZ dose (p <0.05)
a = statistically significant vs. component monotherapy aliskiren dose (p <0.05)
ACE inhibitors and Amlodipine
The combination of Rasilez * and the ACE inhibitor ramipril 10 mg lowered blood pressure to a greater extent than either monotherapy as shown in Table 5. Rasilez * also provided additional blood pressure reduction when co-administered with amlodipine 5 mg in one study, but the combination was not statistically significantly better than amlodipine 10 mg (see Table 6).
Ramipril 10 mg N=275
Aliskiren 300 mg N=279
Ramipril 10 mg + Aliskiren 300 mg N=274
SBP/DBP mm Hg 12/10.7 14.7a/11.3 16.6&/12. 8# @
ap=0.02 vs. Ramipril; &p<.0001 vs. Ramipril; #p=0.004 vs. Ramipril; @p=0.04 vs. Aliskiren
Amlodipine 5 mg N=177
Amlodipine 10 mg N=177
Aliskiren 150 mg + Amlodipine 5 mg N=187
SBP/DBP mm Hg 5.0/4.8 9.6/8.0 11a/8.5a
ap<0.0001 vs Amlodipine 5 mg
Double transgenic rats exhibit fulminant hypertension and end-organ damage as a result of an over-stimulated RAS. Because these animals express human genes for renin and angiotensinogen, they are well suited to test human renin inhibitors for organ protective effects. Accordingly, aliskiren was tested in dTGR for its ability to inhibit renal and cardiac damage that ensues in this model.
The dose-response profile for the antihypertensive effects of aliskiren was defined in dTGR. Two methods of continuous, direct BP monitoring in conscious, unrestrained animals were utilized: (i) radiotelemetry, and (ii) chronic catheterization of the femoral artery and vein. In the latter model, the femoral vein was also chronically catheterized for infusion of test agents and withdrawal of blood. Aliskiren induces a dose-dependent reduction in MAP following single i.v. and p.o. doses administration. Responses to aliskiren under various dosing regimen were compared to those for the angiotensin receptor blocker (ARB) valsartan and/or the ACE inhibitor enalapril(at) in dTGRs. Aliskiren administered i.v. was approximately equipotent with i.v. valsartan and enalapril, whereas with po administration, aliskiren was less potent due to the lower oral bioavailability of aliskiren compared to the two other agents.
The 24-hour mean urinary albumin excretion (UAE) before randomization averaged 2.0 +- 0.2 mg/day in all dTGR groups. This level of UAE reflects a significant elevation (p<0.05) compared to historical values seen in normal Sprague-Dawley control rats (0.2 +- 0.05 mg/day). At 7 weeks of age, UAE in vehicle-treated dTGR was increased to 36.4 +- 4.6 mg/day. In contrast, in the 0.3 and 3 mg/kg/day aliskiren treated groups, albuminuria decreased at nine weeks (p<0.05) to 1.6 +- 0.6 mg/day or 0.4 +- 0.2 mg/day, respectively.
In the dTGR model, cardiac hypertrophy and left ventricular wall thickness were significantly (p< 0.05) reduced in the aliskiren treated groups (0.3 and 3mg/kg/day) and in the valsartan 10mg/kg/day group compared to the low dose valsartan group (1mg/kg/day). Tissue Doppler measurements showed improved early and late diastolic inflow quotient (Ea/Aa) in both aliskiren groups and in the 10 mg/kg/day valsartan group, demonstrating improved diastolic filling.
The effect of aliskiren on the renal fibrosis observed in dTGR was assessed by immunostaining for collagen IV in kidney sections. Semi-quantitative evaluation showed that both aliskiren doses and 3mg/kg/day) and valsartan 10 mg/kg/day suppressed collagen IV immunostaining of Bowman's capsule and tubular basement membranes relative to that observed in the valsartan 1 mg/kg/day group. Renal inflammation, evidenced by the infiltration of macrophages and T-cells, is typically present in the kidneys of dTGR. Aliskiren 0.3 and 3mg/kg/day and valsartan 10mg/kg/d completely prevented the renal accumulation of these inflammatory markers, presumably by inhibiting the formation of Ang II at the local (tissue) level. In a separate study, four weeks old dTGR were treated with aliskiren (3 mg/kg/day, subcutaneous osmotic mini-pumps) or losartan (10 mg/kg/day in the diet) for three weeks. During the progression of hypertension, untreated dTGR exhibited increases in serum and renal inflammatory markers: serum C-reactive protein, renal TNF-a, and various components of complement, including the membrane attack complex C5b-9. Aliskiren as well as losartan suppressed the expression of these markers of inflammation, as assessed by immunostaining.
No adverse findings were noted at doses of 1000 or 2000 mg/kg. It was concluded that the acute oral toxicity (LD50) of aliskiren in rats is higher than 2000 mg/kg.
Exposure to aliskiren at the no-observed-adverse-effect levels (NOAEL) in the repeat dose toxicity studies was generally similar to or less than that in humans at 300 mg. The doses in rodents were limited by local respiratory irritation following aspiration of the dosing solutions. In marmosets, altered kidney function and early deaths as a result of marked hypotension were the main dose-limiting effects during the chronic toxicity studies but these were attributable to the expected pharmacology of aliskiren. These limitations prevented the animal toxicology studies from obtaining high multiples of human exposure. Nevertheless, no target organ toxicities relevant for human use were observed during the chronic toxicity studies at doses up to 600 mg/kg/day in rats or 50 mg/kg/day in marmosets which correspond to systemic exposures based on mean AUC of approximately 3 and 46-fold higher, respectively than those observed in humans at the dose of 300 mg.
Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic mouse study. No carcinogenic potential was detected. Inflammatory and proliferative changes were observed in the lower gastro-intestinal tract at doses of 750 or 1500 mg/kg/day in both species. These findings were attributed to the known irritation potential of aliskiren. One colonic adenoma and one cecal adenocarcinoma also recorded in rats at the dose of 1500 mg/kg/day were not statistically significant. Safety margins based on local, intra-intestinal exposure obtained in humans at the dose of 300 mg during a study in healthy volunteers were 9-11-fold based on fecal concentrations, and 6-fold based on rectal mucosa concentrations compared to exposures at a dose of 250 mg/kg/day in the rat carcinogenicity study. On a systemic exposure (AUC 0-24hr) basis, 1500 mg/kg/day in the rat study resulted in plasma levels 4- to 5-fold higher than those following the maximum recommended human dose of 300 mg o.d.
Aliskiren fumarate was devoid of any mutagenic potential in the in vitro and in vivo mutagenicity studies. The assays included in vitro assays in bacterial and mammalian cells and in vivo assessments in rats.
Reproductive toxicity studies did not reveal any evidence of embryofetal toxicity or teratogenicity at doses up to 600 mg/kg/day in rats or 100 mg/kg/day in rabbits. These doses result in plasma levels 3- and 5-fold higher than those following the maximum recommended dose in humans (300 mg). Fertility, pre-natal development and post-natal development were unaffected in rats at doses up to 250 mg/kg/day, resulting in plasma levels comparable to those following the maximum recommended dose in humans.
Drummond W, Munger MA, Essop MR, et al. Antihypertensive efficacy of the oral direct renin inhibitor aliskiren as add-on therapy in patients not responding to amlodipine monotherapy. J Clin Hypertens 2007; 9: 742-750.
Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005; 111(8):1012-8.
Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension 2002; 39(1): E1-8.
Oh BH, Mitchell J, Herron JR, Chung J, Khan M, Keefe DL. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. Journal of the American College of Cardiology 2007; 49 (11): 1157-1163.
Pilz B, Shagdarsuren E, Wellner M, Fiebeler A, Dechend R, Gratze P, Meiners S, Feldman DL, Webb RL, Garrelds IM, Jan Danser AH, Luft FC, Muller DN. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double- transgenic rats. Hypertension 2005; 46(3):569-76.
Shagdarsuren E, Wellner M, Braesen JH, Park JK, Fiebeler A, Henke N, Dechend R, Gratze P, Luft FC, Muller DN. Complement Activation in Angiotensin II-Induced Organ Damage. Circ Res 2005; 97(7):716-24.
Villamil A, Chrysant S, Calhoun D, et al. The novel oral renin inhibitor aliskiren provides effective blood pressure control in patients with hypertension when used alone or in combination with hydrochlorothiazide. [American Society of Hypertension - ASH 2006]. J Clin Hypertens 2006; 8(5 Suppl. A): A100(P-228).
Weir MR, Bush C, Anderson DR, et al. Antihypertensive efficacy, safety, and tolerability of the oral direct renin inhibitor aliskiren in patients with hypertension: a pooled analysis. Journal of the American Society of Hypertension 2007; 1(4):264-277.
Wood JM, Schnell CR, Cumin F, Menard J, Webb RL. Aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats. J Hypertens 2005; 23(2):417-26.
IMPORTANT: PLEASE READ
PART III: CONSUMER INFORMATION
Pr
Rasilez *
aliskiren (as aliskiren fumarate)
This leaflet is part III of a three-part "Product Monograph" published when Rasilez * was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about Rasilez *. Contact your doctor or pharmacist if you have any questions about the drug.
ABOUT THIS MEDICATION
What the medication is used for:
Rasilez * is a medication that helps to control hypertension (high
blood pressure).
High blood pressure increases the workload of the heart and arteries. If this condition continues for a long time, damage to the blood vessels of the brain, heart, and kidneys can occur, and may eventually result in a stroke, heart failure or kidney failure. High blood pressure also increases the risk of heart attacks. Reducing your blood pressure decreases your risk of developing these illnesses.
What it does:
Rasilez * belongs to a new class of medicines called "direct renin
inhibitors", which help to control high blood pressure. Rasilez * works differently than other anti-hypertensive agents. It can be used alone or in combination with selected other agents to get a better reduction of the blood pressure. Renin inhibitors prevent the body from producing angiotensin II, a substance that causes blood vessels to tighten, thus increasing blood pressure. As a result, blood vessels relax and blood pressure is lowered.
When it should not be used:
You should not take Rasilez * if:
You have ever had an unusual or allergic reaction to aliskiren or to any other component of this product (see below)
You are pregnant or plan to become pregnant
You are breastfeeding
Rasilez * is not recommended for use in patients under 18 years of age.
What the medicinal ingredient is:
The medicinal ingredient is aliskiren.
What the important nonmedicinal ingredients are:
Rasilez * also contains the following non-medicinal ingredients: microcrystalline cellulose, crospovidone, povidone, magnesium
stearate, silica colloidal anhydrous, macrogol, talc, hypromellose,
titanium dioxide (E171), red iron oxide (E172), black iron oxide (E172).
What dosage forms it comes in:
Rasilez * is available as 150 and 300 mg coated tablets.
WARNINGS AND PRECAUTIONS
Serious Warning and Precaution
Rasilez * should not be used during pregnancy. If you discover that you are pregnant while taking Rasilez *, stop the medication and contact your physician as soon as possible.
BEFORE you use Rasilez * talk to your doctor or pharmacist if:
You have or have had an impaired kidney function.
You have gastro-intestinal problems
You are on a salt restricted diet
You are already taking another medicine to lower blood pressure
You are pregnant, think you may have become pregnant or are planning to become pregnant
You are breastfeeding
You are taking cyclosporine (a medicine used in transplantation to prevent organ rejection or for other conditions, e.g. rheumatoid arthritis or atopic dermatitis)
If any of these apply to you, tell your doctor before you take Rasilez *.
Pregnant women
Do not take Rasilez * if you are pregnant. Similar medicines were associated with serious harm to fetuses when they were
taken during pregnancy. It is therefore important to tell your
doctor immediately if you think you may have become pregnant, or planning to become pregnant.
Breast-feeding mothers
Although it is not known whether Rasilez * can pass into human breast milk, this does happen in animals. Tell your doctor if you
are breast-feeding. You should not breast-feed if you are taking Rasilez *, as it might be harmful for your infant.
INTERACTIONS WITH THIS MEDICATION
Tell your doctor or pharmacist about any medicines you are taking or have recently taken, including prescription medications (the ones your doctor writes for you) and over-the-counter medications (the ones you buy in the drugstore, like cold or allergy medicines), or natural health products (herbal medicines).
Drugs that may interact with Rasilez *:
Furosemide, a medicine used to increase the amount of urine (diuretic)
Irbesartan, a medicine used to also lower the blood pressure
Ketoconazole, a medicine used to treat fungal infections
Cyclosporine, a medicine used to prevent graft rejection or for other conditions, e.g. rheumatoid arthritis or atopic dermatitis (red, flaky, itchy skin)
Potassium-sparing diuretics, potassium-containing medicines, potassium supplements, or salt substitutes containing potassium
PROPER USE OF THIS MEDICATION
Remember that this medicine does not cure your high blood pressure; it only may help to control it. Therefore, if you want to lower your blood pressure and keep it down, you must continue to take Rasilez * as directed.
Patients who have high blood pressure often do not notice any signs or symptoms of this condition. Indeed, many may feel quite normal for a long time. So even though you are feeling well, your health may be getting worse. This makes it all the more important for you to continue your treatment program and to keep your appointments with your doctor.
Usual dose:
The usual starting dose is one 150 mg tablet once a day. In some
cases, your doctor may prescribe a higher dose (e.g. 300 mg tablet) or an additional medicine used to treat high blood pressure. Rasilez * may be used over a dosage range of 150 mg to 300 mg once daily. Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose.
How to use Rasilez *:
Follow your doctor's instructions carefully. Do not exceed the recommended dose (300 mg once daily).
When and how to take Rasilez *:
Swallow Rasilez * tablets whole with a small amount of water. Do not chew or crush the tablets. You can take Rasilez * with or without food, but it should be taken the same way each day and at the same time.
How long to take Rasilez *:
Follow your doctor's instructions exactly. Your doctor will tell you for how long you should take Rasilez *.
Overdose:
If you have accidentally taken too many tablets, seek medical assistance immediately.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
Missed Dose:
If you miss a dose of this medicine, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
some people. The following side effects have been reported with patients taking Rasilez *:
Nasopharyngitis (common cold)
diarrhea
edema (accumulation of fluid in tissues that can cause swelling)
constipation
headache
dizziness
fatigue
influenza
back pain
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
| SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM | ||||
| Symptom / effect | Talk with your doctor or pharmacist | Stop taking drug and call your doctor or pharmacist SS | ||
| Only if severe | In all cases | |||
| Uncommon | Severe diarrhea | 9 | ||
| Uncommon | Swelling of the face, nose, lips or tongue that can lead to discomfort when swallowing or difficulty in breathing | 9 | ||
SS If you think you have these side effects, it is important that you seek medical advice from your doctor immediately.
This is not a complete list of side effects. For any unexpected effects while taking Rasilez *, contact your doctor or pharmacist.
HOW TO STORE IT
Do not store above 30degC.
Do not use after the expiry date shown on the box.
Store in the original package in order to protect from moisture.
Keep out of the reach and sight of children.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
Like all medicines, Rasilez * may cause unwanted side effects in
IMPORTANT: PLEASE READ
REPORTING SUSPECTED SIDE EFFECTS
To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:
toll-free telephone: 866-234-2345
toll-free fax 866-678-6789 By email: CanadaVigilance @hc-sc.gc.ca
By regular mail:
Canada Vigilance National Office
Marketed Health Products Safety and Effectiveness Information Bureau
Marketed Health Products Directorate Health Products and Food Branch Health Canada
Tunney's Pasture, AL 0701C
Ottawa ON K1A 0K9
NOTE:
Should you require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.
MORE INFORMATION
Please consult your doctor or pharmacist with any questions or concerns you may have regarding your individual condition.
This document plus the full product monograph, prepared for health professionals can be found at:
http://www.novartis.ca
or by contacting the sponsor,
Novartis Pharmaceuticals Canada Inc., at:
1-800-363-8883
This leaflet was prepared by Novartis Pharmaceuticals Canada Inc. Novartis Pharmaceuticals Canada Inc.,
385 Bouchard, Dorval, QC H9S 1A9 Last revised: March 13, 2008
* Rasilez is a registered trademark