RIVA-TELMISARTAN/AMLODIPINE

). 1 Pediatrics • Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of telmisartan/amlodipine besylate in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

2 Geriatrics • Geriatrics (> 65 years of age): No dose adjustment is necessary for geriatric patients. It should be recognized, however, that greater sensitivity in some older individuals cannot be ruled out. 73m2) is contraindicated (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Dual Blockade of the Renin- Angiotensin System (RAS) and Renal, and 9 DRUG INTERACTIONS, Dual Blockade of the Renin- Angiotensin System (RAS) with ACEIs, ARBs or aliskiren-containing drugs).

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the

1 Adverse Reaction Overview Summary of the safety profile The safety and tolerability of telmisartan/amlodipine besylate has been evaluated in five controlled clinical studies with over 3500 patients, over 2500 of whom received telmisartan in combination with amlodipine.

No additional adverse reactions were identified in clinical trials with the combination telmisartan plus amlodipine compared to the adverse reactions of the monocomponents. Peripheral oedema, a recognized dose dependent adverse reaction of the monocomponent amlodipine, was generally observed at a lower incidence in patients who received the telmisartan/amlodipine combination than in those who received amlodipine alone.

Adverse reactions previously reported with one of the monocomponents (telmisartan or amlodipine) may be potential adverse reactions with telmisartan/amlodipine besylate as well, even if not observed in clinical trials or during the post-marketing period.

Therefore, in addition to the reported adverse reactions during the telmisartan/amlodipine besylate development program all adverse reactions reported in patients who received telmisartan or amlodipine monotherapy, have been listed for telmisartan/amlodipine besylate.

2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. g. hypotension, orthostatic hypotension, syncope) were rare throughout the double-blind treatment period of a randomized, double- dummy, placebo- controlled 4 x 4 factorial design trial, including the initial 2 weeks of first-line combination therapy.

There were no serious cases. Almost all of the events were of mild or moderate intensity, and the majority of patients continued treatment and recovered without requiring therapy. In a single, randomized double-blind placebo controlled, 8-week factorial design comparing free dose combination telmisartan/amlodipine to monotherapy (telmisartan or amlodipine) and placebo, adverse events (AEs) occurred with similar frequency across the treatment groups, with the highest frequency in the telmisartan 80mg/amlodipine 5 mg (T80/A5) group but the incidence of all AEs, in all groups was within 4% of the placebo group.

Three serious adverse events occurred in the T80/A5 group, none of which were felt to be drug related. The three serious adverse events occurred in 3 different patients and included multiple fractures, deep venous thrombosis, and chest pain (see Table 2).

Table 2:

Summary of adverse events by overall treatment groups in the factorial study. T40/A5 T40/A10 T80/A5 T80/A10 T40 T80 A5 A10 Placebo n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Incidence over entire study: No. 0) 1 Marked laboratory abnormalities or AEs leading to intervention, other than those considered serious 2 A patient may be counted in more than one seriousness criterion T = Telmisartan 40 or 80 mg; A = amlodipine 5 or 10 mg.

8%). Patient frequencies of some common AEs were higher in some combination groups than in the respective component monotherapy groups, but no consistent patterns were apparent (see Table 3). e. peripheral edema, headache and fatigue), all drug-related AEs were reported by <1% of patients in any treatment group.

Additional data on long term safety was based on an open-label, limited study, of 6 month up to 8 months duration and no new safety signals were noted.

Table 3:

Adverse events with reported incidence ≥2% […]

, Cardiovascular, Dual Blockade of the Renin- Angiotensin System (RAS) and Renal, and 9 DRUG INTERACTIONS, Dual Blockade of the Renin- Angiotensin System (RAS) with ACEIs, ARBs or aliskiren-containing drugs). • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.

For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section of the product monograph. • Patients with a hypersensitivity to dihydropyridine derivatives. • Patients with a known hypersensitivity (anaphylaxis) or angioedema to ARBs (see 7 WARNINGS AND PRECAUTIONS, General).

1 Pregnant Women) o When used in pregnancy, angiotensin receptor (AT1) blockers (ARB) can cause injury or even death of the developing fetus. When pregnancy is detected, RIVA- TELMISARTAN/AMLODIPINE should be discontinued as soon as possible.

2 Breast-feeding). • Patients with biliary obstructive disorders. • Patients with severe hepatic impairment. Product Monograph RIVA-TELMISARTAN/AMLODIPINE (telmisartan/amlodipine) Page 6 of 54 • Patients with shock including cardiogenic shock.

• Severe hypotension (less than 90 mmHg systolic). g. high grade aortic stenosis). • Haemodynamically unstable heart failure after acute myocardial infarction. • Patients with rare hereditary conditions that may be incompatible with an excipient of the product.

• Patients with the rare hereditary condition of fructose intolerance (HFI) o Mannitol: Mannitol is a source of fructose. 72 mg of mannitol in each tablet respectively. o Meglumine: Meglumine is a source of fructose. 80 mg of meglumine in each tablet respectively.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX Serious Warnings and Precautions When used in pregnancy, angiotensin receptor (AT1) blockers (ARB) can cause injury or even death of the developing fetus. 1 Special Populations). 1 Dosing Considerations Patients should be titrated on individual drugs.

If the fixed dose combination represents the dose and dosing frequency determined by this titration, the use of RIVA-TELMISARTAN/AMLODIPINE may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary, it is advisable to use the individual drugs.

2 Recommended Dose and Dosage Adjustment • RIVA-TELMISARTAN/AMLODIPINE should be taken once daily. • If during maintenance therapy dosage adjustment is necessary, it is advisable to use the individual drugs. g. to enhance convenience.

Special populations Renal impairment No dosage adjustment is required for patients with renal impairment, including those on haemodialysis. Product Monograph RIVA-TELMISARTAN/AMLODIPINE (telmisartan/amlodipine) Page 7 of 54 Hepatic impairment In patients with mild to moderate hepatic impairment RIVA-TELMISARTAN/AMLODIPINE should be administered with caution.

For telmisartan the dosage should not exceed 40 mg once daily as hepatic impairment increases bioavailability (see Special Populations and Conditions - Hepatic insufficiency). Amlodipine dosage requirement have not been established in patients with impaired hepatic function.

When amlodipine is used in these patients, it should be initiated at the lower end of the dosing range and the dosage should be carefully and gradually adjusted depending on the patient’s tolerance and response. Geriatrics (> 65 years of age) No dose adjustment is necessary for elderly patients.

It should be recognized, however, that greater sensitivity in some older individuals cannot be ruled out. If required, increase in the dose should be done gradually and with caution (see 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY).

Pediatric population (<18 years of age) RIVA-TELMISARTAN/AMLODIPINE is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy. Drug discontinuation If laryngeal stridor or angioedema of the face, extremities, lips, tongue, or glottis occurs, RIVA- TELMISARTAN/AMLODIPINE should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears.

When pregnancy is detected, RIVA-TELMISARTAN/AMLODIPINE should be discontinued as soon as possible. 4 Administration Tablet for oral administration RIVA-TELMISARTAN/AMLODIPINE should be taken consistently with or without food. RIVA- TELMISARTAN/AMLODIPINE tablets are for once-daily oral administration and should be swallowed whole with liquid.

5 Missed Dose If a dose is missed during the day, the next dose should be continued at the usual time. Do not double dose. 5 OVERDOSAGE Symptoms Telmisartan/amlodipine tablets: Signs and symptoms of overdose are expected to be in line with exaggerated pharmacological effects.

Telmisartan:

Limited data are available with regard to telmisartan overdosage in humans. The most prominent manifestations of overdosage were hypotension and/or tachycardia; bradycardia also occurred. Product Monograph RIVA-TELMISARTAN/AMLODIPINE (telmisartan/amlodipine) Page 8 of 54 It is not known if telmisartan can be removed from the body by hemodialysis.

Amlodipine:

Overdose with amlodipine may result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and […]

73m2) is contraindicated (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Dual Blockade of the Renin- Angiotensin System (RAS) and Renal, and 9 DRUG INTERACTIONS, Dual Blockade of the Renin- Angiotensin System (RAS) with ACEIs, ARBs or aliskiren-containing drugs).

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section of the product monograph.

• Patients with a hypersensitivity to dihydropyridine derivatives. • Patients with a known hypersensitivity (anaphylaxis) or angioedema to ARBs (see 7 WARNINGS AND PRECAUTIONS, General). 1 Pregnant Women) o When used in pregnancy, angiotensin receptor (AT1) blockers (ARB) can cause injury or even death of the developing fetus.

When pregnancy is detected, RIVA- TELMISARTAN/AMLODIPINE should be discontinued as soon as possible. 2 Breast-feeding). • Patients with biliary obstructive disorders. • Patients with severe hepatic impairment. Product Monograph RIVA-TELMISARTAN/AMLODIPINE (telmisartan/amlodipine) Page 6 of 54 • Patients with shock including cardiogenic shock.

• Severe hypotension (less than 90 mmHg systolic). g. high grade aortic stenosis). • Haemodynamically unstable heart failure after acute myocardial infarction. • Patients with rare hereditary conditions that may be incompatible with an excipient of the product.

• Patients with the rare hereditary condition of fructose intolerance (HFI) o Mannitol: Mannitol is a source of fructose. 72 mg of mannitol in each tablet respectively. o Meglumine: Meglumine is a source of fructose. 80 mg of meglumine in each tablet respectively.