Additional 4.1 text shown in bold

4.1       Therapeutic indications

 

Treatment of essential hypertension in adults.

Treatment of hypertension in children and adolescents from 6 to less than 18 years of age.

 

Additional 4.2 text shown in bold – deleted shown in strike-through

4.2       Posology and method of administration

 

Posology

…….

Paediatric population

Children and adolescents from 6 to less than 18 years of age:

The recommended starting dose of olmesartan medoxomil in children from 6 to less than 18 years of age is 10 mg olmesartan medoxomil once daily. In children whose blood pressure is not adequately controlled at this dose, the dose of olmesartan medoxomil may be increased to 20 mg once daily. If additional blood pressure reduction is required, in children who weigh ≥ 35 kg, the olmesartan medoxomil dose may be increased to a maximum of 40 mg. In children who weigh < 35 kg, the daily dose should not exceed 20 mg.

Other paediatric population:

The safety and efficacy of olmesartan medoxomil in children aged 1 to 5 years old and adolescents below 18 years has have not yet been established. Currently available data are described in sections 4.8 and 5.1 and 5.2 but no recommendation on a posology can be made.

 

…….

 

Additional 4.5 text shown in bold – deleted shown in strike-through

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Interaction studies have only been performed in adults.

……..

 

Paediatric population:

Interaction studies have only been performed in adults.

It is not known if the interactions in children are similar to those in adults.

 

Additional 5.1 text shown in bold – deleted shown in strike-through

 

5.1       Pharmacodynamic properties

 

……..

 

Paediatric population

 

 

The antihypertensive effects of olmesartan medoxomilBenetor in the paediatric population were evaluated in a randomized, double-blind, placebo-controlled study in 302 hypertensive patients aged 6 to 17 years. The study population consisted of an all black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks. The etiology of the hypertension was predominantly essential hypertension (87% of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized to 2.5 mg (low dose) or 20 mg (high dose) of olmesartan medoxomilBenetor once daily and patients who weighed ≥35 kg were randomized to 5 mg (low dose) or 40 mg (high dose) of olmesartan medoxomilBenetor once daily. olmesartan medoxomilBenetor significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner. olmesartan medoxomilBenetor at both low and high doses significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline, respectively. This effect was also observed during the 2 weeks randomized withdrawal phase, whereby both mean systolic and diastolic blood pressures demonstrated a statistically significant rebound in the placebo group compared to olmesartanBenetor group. The treatment was effective in both, paediatric patients with primary and secondary hypertension. As observed in adult populations, the blood pressure reductions were smaller in black patients.

In the same study, 59 patients aged 1 to 5 years who weighed ≥5 kg received 0.3 mg/kg of olmesartan medoxomilBenetor once daily for three weeks in an open label phase and then were randomized to receiving olmesartan medoxomilBenetor or placebo in a double-blind phase. At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group randomized to olmesartan medoxomilBenetor; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7).

Additional 10 text shown in bold – deleted shown in strike-through

 

10.       DATE OF (PARTIAL) REVISION OF THE TEXT

 

03/201702/2016

 

Additional 4.2 text shown in bold – deleted shown in strike-through

4.2       Posology and method of administration

 

Posology:

……

 

Elderly Older people (65 years or older over)

 

No adjustment of dosage is generally required in elderly older people (see below for dose recommendations in patients with renal impairment). If up-titration to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.

…….

 

Additional 4.4 text shown in bold – deleted shown in strike-through

4.4       Special warnings and precautions for use

 

…….

Renal impairment and kidney transplantation:

When olmesartan medoxomil is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min) (see sections 4.2, 5.2). There is no experience of the administration of olmesartan medoxomil in patients with a recent kidney transplant or in patients with end-stage renal impairment (ie i.e. creatinine clearance <12 mL/min).

……..

Hyperkalaemia:

The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia.

The risk, that may be fatal, is increased in elderly older people, in patients with renal insufficiency and in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.

……..

Sprue-like enteropathy:

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in the absence of other apparent etiologies, olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.exclude other etiologies. Consider discontinuation of olmesartan medoxomil in cases where no other etiology is identified. In cases where symptoms disappear and sprue-like enteropathy is confirmed by biopsy, treatment with olmesartan medoxomil should not be restarted.

……..

 

Additional 4.8 text shown in bold

4.8       Undesirable effects

 

…….

 

Tabulated list of adverse reactions:

 

Adverse reactions from Benetor in clinical trials, post-authorisation safety studies and spontaneous reporting are summarized in the below table.

 

The following terminologies have been used in order to classify the occurrence of adverse reactions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

 

……..

Additional 5.2 text shown in bold – deleted shown in strike-through

 

5.2       Pharmacokinetic properties

 

……..

 

Pharmacokinetics in special populations

Paediatric population:

The pharmacokinetics of olmesartan was studied in paediatric hypertensive patients aged 1 to 16 years. The clearance of olmesartan in paediatric patients was similar to that in adult patients when adjusted by the body weight.

There is no pharmacokinetic information available in renally impaired paediatric subjects.

Elderly Older people (age 65 years or older over):

In hypertensive patients, the AUC at steady state was increased by ca 35% in elderly older people (65 – 75 years old) and by ca 44% in very elderly old people (³ 75 years old) compared with the younger age group. This may be at least in part related to a mean decrease in renal function in this group of patients.

 

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Additional 10 text shown in bold – deleted shown in strike-through

 

10.       DATE OF (PARTIAL) REVISION OF THE TEXT

 

02/201601/2016

 

……….

 

 

Additional 4.2 text shown in bold – deleted shown in strike-through

4.2     Posology and method of administration

 

Posology:

…….

Paediatric population

The safety and efficacy of Benetor olmesartan medoxomil in children and adolescents below 18 years has not been established. No data are available. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Olmesartan medoxomil should not be used in children below 1 years of age because of safety concerns and lack of data in this age group.

…….

 

Additional 4.8 text shown in bold – deleted shown in strike-through

4.8     Undesirable effects

 

…….

Additional information on special populations

Paediatric population

The safety of olmesartan medoxomil was monitored in 361 children and adolescents, aged 1-17 years old during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:

-          Epistaxis is a common adverse event in children (i.e. ≥ 1/100 to < 1/10) that has not been reported in adults.

-          During the 3 weeks of double blind study, the incidence of treatment emergent dizziness and headache nearly doubled in children 6-17 years of age in the high olmesartan medoxomil dose group.

The overall safety profile for olmesartan medoxomil in paediatric patients does not differ significantly from the safety profile in adults.

Elderly (age 65 years or over)

In older elderly people the frequency of hypotension is slightly increased from rare to uncommon.

……..

 

Additional 5.1 text shown in bold

5.1     Pharmacodynamic properties

 

……..

Paediatric population

The antihypertensive effects of Benetor in the paediatric population were evaluated in a randomized, double-blind, placebo-controlled study in 302 hypertensive patients aged 6 to 17 years. The study population consisted of an all black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks. The etiology of the hypertension was predominantly essential hypertension (87% of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized to 2.5 mg (low dose) or 20 mg (high dose) of Benetor once daily and patients who weighed ≥35 kg were randomized to 5 mg (low dose) or 40 mg (high dose) of Benetor once daily. Benetor significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner. Benetor at both low and high doses significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline, respectively. This effect was also observed during the 2 weeks randomized withdrawal phase, whereby both mean systolic and diastolic blood pressures demonstrated a statistically significant rebound in the placebo group compared to Benetor group. The treatment was effective in both, paediatric patients with primary and secondary hypertension. As observed in adult populations, the blood pressure reductions were smaller in black patients.

In the same study, 59 patients aged 1 to 5 years who weighed ≥5 kg received 0.3 mg/kg of Benetor once daily for three weeks in an open label phase and then were randomized to receiving Benetor or placebo in a double-blind phase. At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group randomized to Benetor; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7).

 

………

 

Additional 5.2 text shown in bold

5.2     Pharmacokinetic properties

 

……….

Pharmacokinetics in special populations

Paediatric population:

The pharmacokinetics of olmesartan was studied in paediatric hypertensive patients aged 1 to 16 years. The clearance of olmesartan in paediatric patients was similar to that in adult patients when adjusted by the body weight.

There is no pharmacokinetic information available in renally impaired paediatric subjects.

……..

 

 

Additional 10 text shown in bold – deleted shown in strike-through

10.     DATE OF (PARTIAL) REVISION OF THE TEXT

 

01/2016 February 2015

 

Additional 4.3 text shown in bold

4.3     Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

Biliary obstruction (see section 5.2).

The concomitant use of Benetor with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections 4.5 and 5.1).

 

Additional 4.4 text shown in bold

4.4     Special warnings and precautions for use

Hyperkalaemia:

The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia.

The risk, that may be fatal, is increased in older people, in patients with renal insufficiency and in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.

Before considering the concomitant use of medicinal products that affect the renin-angiotensin- aldosterone system, the benefit risk ratio should be evaluated and other alternatives considered (see also below section “Dual blockade of the renin-angiotensin-aldosterone system (RAAS)”).

The main risk factors for hyperkalaemia to be considered are:

-  Diabetes, renal impairment, age (> 70 years)

-  Combination with one or more other medicinal products that affect the renin-angiotensin- aldosterone system and/or potassium supplements. Some medicinal products or therapeutic class of medicinal products may provoke a hyperkalaemia: salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptors antagonists, non steroidal anti-inflammatory drugs (including selective COX-2 inhibitors), heparin, immunosuppressor as ciclosporin or tacrolimus, trimethoprim.

-  Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g, acute limb ischemia, rhabdomyolysis, extended trauma).

Close-monitoring of serum potassium in at risk patients is recommended (see section 4.5).

 

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

 

Additional 4.5 text shown in bold – deleted shown in strike-through

4.5     Interaction with other medicinal products and other forms of interaction

 

Interaction studies have only been performed in adults.

Effects of other medicinal products on olmesartan medoxomil:

Other antihypertensive medications:

The blood pressure lowering effect of olmesartan medoxomil can be increased by concomitant use of other antihypertensive medications.

ACE-inhibitors, angiotensin II receptor blockers or aliskiren:

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Potassium supplements and potassium sparing diuretics: 

Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium (see section 4.4). Such concomitant use is therefore not recommended.

Other antihypertensive medications: 

The blood pressure lowering effect of olmesartan medoxomil can be increased by concomitant use of other antihypertensive medications.

 

Additional 5.1 text shown in bold

5.1     Pharmacodynamic properties

 

Other information:

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

 

Revised 10 text shown in bold

10.     DATE OF (PARTIAL) REVISION OF THE TEXT

 

February 2015

 

Update following approval of WS/097: Colesevelam

Update following Roadmap/Sprue like enteropathy

In section 2 (Qualitative and Quantitative Composition) - The quantity of lactose monohydrate is included in this section for each strength.
In Section 4.2 (Posology and method of administration) - The tablets should be swallowed with a sufficient amount of water (e.g. one glass). The tablets should not be crushed.
In Section 4.7 (Effects on the ability to drive and use machines) - Benetor has minor or moderate influence on the ability to drive and use machines. Dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react.
In Section 4.8 (Undesireable effects) - Updated in line with MedRA System Organ Class
In Section 10 (Date of revision) - Updated to April 2013

In section 4.3, the contraindication of "lactation" has been deleted.

Under section 4.6, "Pregnancy and Lactation", the wording has been amended to advise that because no information is available on the use of Benetor during breast-feeding, that breast-feeding is not recommended.

Section 10 has been updated to reflect the revised date of revision of the text.

Under Section 3:  Pharmaceutical Form, the information relating to the 20mg and 40mg tablets has been added as follows: 

Benetor 10 and 20 mg tablets: White, circular, film-coated tablets with C13 and C14 respectively embossed on one side.

Benetor 40 mg tablets: White, oval, film-coated tablets with C15 embossed on one side.