Teveten 400mg Film-coated Tablets

In section 6.5, deletion of bottles as immediate packaging container

7.  MARKETING AUTHORISATION HOLDER

Mylan IRE Healthcare Limited

Unit 35/36

Grange Parade

Baldoyle Industrial Estate

Dublin 13

Ireland

BGP Products Ireland Limited

4051 Kingswood Drive,

Citywest Business Campus,

Dublin 24

8. MARKETING AUTHORISATION NUMBER

 

PA 2010/17/1 2007/14/1

10. DATE OF REVISION OF THE TEXT

 

June 2017

Section 7:
MA Holder changed from Abbott Healthcare Products Limited to BGP Products Ltd

Section 8:
PA Number changed from PA 108/23/3 to PA 2007/14/1

Section 4.3 Contraindications
Addition of bullet point - The concomitant use of Teveten with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GRF < 60ml/min/1.73 m²) (see section 4.5 and 5.1)

Section 4.4 Special warnings and precautions for use
Addition of a separate paragraph in relation to Doal blockade of the renin-angiotensin-aldosterone system (RAAS)
Updating "Eprosartan" with "angiotensin II receptor blockers"

Section 4.5 Interaction with other medicinal products and other forms of interaction
Deletion of the following paragraphs:
"No effect on the pharmacokinetics of digoxin and the pharmacodynamics of warfarin or glyburide (glibenclamide) has been shown with eprosartan.  Similarly no effect on eprosartan pharmacokinetics has been shown with ranitidine, ketoconazole or fluconazole"
"Eprosartan can be used concomitantly with thiazide diuretics (e.g. hydrochlorothiazide) and calcium channel blockers (e.g. sustained-release nifedipine) without evidence of clinically significant adverse interactions"

Addition of the following paragraph:
"Clinical trial data has shown that dual-blockade of the renin-angiotensis-alderstone-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)"    
 
Section 4.6 Pregnancy and lactation
Updating "eprosartan" with "angiotensin II receptor blockers"

Section 4.8 Undesirable Effects
Updating with a paragraph in relation to Reporting of Suspected Adverse Reactions

Section 5.1 Pharmacodynamic Pproperties
Addition of a paragraph in relation to two large randomised, controlled trials - ONTARGET and ALTITUDE

Section 5.3 Preclinical safety data
Removal of the following line in relation to Reproductive and Developmental toxicity in pregnant rabbits
"This is most likely due to effects on the renin-angiotensin aldosterone system"

Section 7 changed:
 
from:

Abbott Healthcare Products Limited.,
Mansbridge Road
West End
Southampton
So18 3JD
UK

to:

Abbott Healthcare Products Limited.,

Abbott House,

Vanwall Business Park,

Vanwall Road,

Maidenhead,

SL6 4XE,

UK.

The following sentence has been added to section 4.9 Overdose:

There have been individual reports from postmarketing experience where doses up to 12,000 mg had been ingested. Most patients reported no symptoms. In one subject circulatory collapse occurred after ingestion of 12,000 mg eprosartan, the subject recovered completely.

Update of sections 4.4, 4.5 & 4.8 of the SPC in line with the EU Core Safety Profile for Eprosartan

In section 6.3, the shelf-life has been changed to 2 years.

Warnngs and precautions concerning use in pregnancy and lactation have been updated and the name of the MAH has changed to reflect new ownership.

In particular, in section 4.3 the product is no longer contra-indicated in lactation although in section 4.6 it is recommended that patients are switched to products with a better established safety profile especially when nursing newborn or preterm infants.

The information on the use during pregnancy (sections 4.4 and 4.6) has been revised by including more detail of the possible risk to the foetus to enable prescribers to make a better informed treatment decision.

In section 7, the name of the MAH has been changed to Abbott Healthcare Products Ltd.

sec.2 present
One film-coated tablet contains eprosartan mesylate, equivalent to 400 mg eprosartan.

For excipients see section 6.1.

sec. 2 propsed

Each film-coated tablet contains eprosartan mesylate equivalent to 400 mg eprosartan.

 

For a full list of excipients, see section 6.1.

sec. 3 present

Film-coated tablet.

Teveten 400 is an oval light pink film-coated tablet imprinted 5044 on one side and SOLVAY on the other

sec. 3 propsed

Film-coated tablet.

 

Oval, light to moderately pink film-coated tablet marked "5044" on one side and "SOLVAY" on the other side.

sec. 4.2 present

The recommended dose is 600 mg Eprosartan once daily.

Achievement of maximal blood pressure reduction in most patients may take 2 to 3 weeks of treatment.

Eprosartan may be used alone or in combination with other anti-hypertensives. In particular, addition of a thiazide-type diuretic such as hydrochlorothiazide or a calcium channel blocker such as sustained release nifedipine has been shown to have an additive effect with Eprosartan.

 

Elderly

No dose adjustment is required in the elderly.

 

Dosage in Hepatically Impaired Patients

There is limited experience in patients with hepatic insufficiency (see Section 4.3 Contraindications).

 

Dosage in Renally Impaired Patients

In patients with moderate or severe renal impairment (creatinine clearance <60 ml/min), the daily dose should not exceed 600 mg.

 

Children

As safety and efficacy in children have not been established, treatment of children is not recommended.

Eprosartan may be taken with or without food.

Duration of treatment is not limited.

sec. 4.2 proposed

The recommended dose is 600 mg eprosartan once daily.

 

Achievement of maximal blood pressure reduction in most patients may take 2 to 3 weeks of treatment.

Eprosartan may be used alone or in combination with other anti-hypertensives. In particular, addition of a thiazide-type diuretic such as hydrochlorothiazide or a calcium channel blocker such as sustained release nifedipine has been shown to have an additive effect with eprosartan.

 

Eprosartan may be taken with or without food.

 

Duration of treatment is not limited.

 

Geriatric patients

 

No dose adjustment is required in the elderly.

 

Dosage in Hepatically Impaired Patients

 

There is limited experience in patients with hepatic insufficiency (see section 4.3).

 

Dosage in Renally Impaired Patients

In patients with moderate or severe renal impairment (creatinine clearance <60 ml/min), the daily dose should not exceed 600 mg.

 

Paediatric patients

Teveten is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

sec. 4.3 present

Known hypersensitivity to eprosartan or to any of the excipients.

Severe hepatic impairment.

Pregnancy and lactation (see Section 4.6 Pregnancy and Lactation).

sec. 4.3 proposed

Known hypersensitivity to eprosartan or to any of the excipients.

Severe hepatic impairment.

Pregnancy and lactation (see section 4.6).

Hemodynamically significant bilateral renovascular disease or severe stenosis of a solitary functioning kidney.

sec. 4.4 present

Hepatic Impairment

There is limited experience in patients with hepatic insufficiency (see Section 4.3 Contraindications).

 

Renal Impairment

No dose adjustment is required in patients with mild to moderate renal insufficiency (creatinine clearance 30 ml/min). Caution is recommended for use in patients with creatinine clearance < 30 ml/min or in patients undergoing dialysis.

 

Coronary Heart Disease

There is limited experience in patients with coronary heart disease at this time.

 

Sodium and/or volume depletion

Symptomatic hypotension may occur in patients with severe volume and/or salt depletion (e.g. high dose diuretic therapy). These conditions should be corrected prior to commencing therapy.

The following precautions have been included based on experience with other agents in this class and also ACE inhibitors:

 

Hyperkalaemia

During treatment with other medicinal products which affect the renin-angiotensin-aldosterone system hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure. Adequate monitoring of serum potassium in patients at risk is recommended.

Based on experience with the use of other medicinal products which affect the renin-angiotensin-aldosterone system, concomitant use with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products which may increase the potassium level (e.g. heparin) may lead to an increase in serum potassium and should therefore be co-administered cautiously with Teveten.

General information (for patients with renal impairment and/or severe cardiac insufficiency)

Patients whose renal function is dependent on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe cardiac insufficiency, bilateral renal artery stenosis, or renal artery stenosis of a solitary kidney) have developed oliguria and/or progressive azotaemia and rarely acute renal failure during therapy with angiotensin converting enzyme (ACE) inhibitors. Since there is currently inadequate therapeutic experience in patients with severe cardiac insufficiency or renal artery stenosis, it cannot be ruled out that renal function in these patients may be impaired with Eprosartan due to inhibition of the renin-angiotensin-aldosterone system. When Eprosartan is used in patients with renal impairment, renal function should be assessed before starting treatment with Eprosartan and at intervals during the course of therapy. If worsening of renal function is observed during therapy, treatment with Eprosartan should be reassessed.

 

Primary Hyperaldosteronism

Patients with primary hyperaldosteronism are not recommended to be treated with Eprosartan.

 

Aortic and Mitral Valve Stenosis / Hypertrophic Cardiomyopathy

As with all vasodilators, Eprosartan should be used with caution in patients with aortic and mitral valve stenosis or hypertrophic cardiomyopathy.

 

Renal Transplantation

There is no experience in patients with recent kidney transplantation.

 

Other warnings and precautions

As observed for angiotensin converting enzyme inhibitors, eprosartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

sec. 4.4 proposed

Hepatic Impairment

 

There is limited experience in patients with hepatic insufficiency (see section 4.3).

 

Renal Impairment

 

No dose adjustment is required in patients with mild to moderate renal insufficiency (creatinine clearance ³ 30 ml/min). Caution is recommended for use in patients with creatinine clearance < 30 ml/min or in patients undergoing dialysis.

 

Renin-angiotensin-aldosterone system dependent patients (see section 4.3)

 

Patients whose renal function is dependent on the activity of the renin-angiotensin­aldosterone system (e.g. patients with severe cardiac insufficiency (NYHA-classification: class IV), bilateral renal artery stenosis, or renal artery stenosis of a solitary kidney) have developed oliguria and/or progressive azotaemia and rarely acute renal failure during therapy with angiotensin converting enzyme (ACE) inhibitors. Since there is currently inadequate therapeutic experience in patients with severe cardiac insufficiency or renal artery stenosis, it cannot be ruled out that renal function in these patients may be impaired with eprosartan due to inhibition of the renin-angiotensin-aldosterone system. When eprosartan is used in patients with renal impairment, renal function should be assessed before starting treatment with eprosartan and at intervals during the course of therapy. If worsening of renal function is observed during therapy, treatment with eprosartan should be reassessed.

 

The following precautions have been included based on experience with other agents in this class and also ACE inhibitors:

 

Hyperkalaemia

During treatment with other medicinal products which affect the renin-angiotensin­aldosterone system hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure. Adequate monitoring of serum potassium in patients at risk is recommended.

 

Based on experience with the use of other medicinal products which affect the renin­angiotensin-aldosterone system, concomitant use of with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products which may increase the potassium level (e.g. heparin) may lead to an increase in serum potassium and should therefore be co-administered cautiously with Teveten.

 

Primary Hyperaldosteronism

 

Patients with primary hyperaldosteronism are not recommended to be treated with eprosartan.

 

Sodium and/or volume depletion

 

Symptomatic hypotension may occur in patients with severe volume and/or salt depletion (e.g. high dose diuretic therapy). These conditions should be corrected prior to commencing therapy.

 

Coronary Heart Disease

 

There is limited experience in patients with coronary heart disease at this time.

 

Aortic and Mitral Valve Stenosis / Hypertrophic Cardiomyopathy

 

As with all vasodilators, eprosartan should be used with caution in patients with aortic and mitral valve stenosis or hypertrophic cardiomyopathy.

 

Renal Transplantation

 

There is no experience in patients with recent kidney transplantation.

 

Other warnings and precautions

 

As observed for angiotensin converting enzyme inhibitors, eprosartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

 

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

sec. 4.5 present

Since in placebo-controlled clinical studies significantly elevated serum potassium concentration were observed, and based on experience with the use of other drugs that affect the renin-angiotensin-aldosterone system, concomitant use of K-sparing diuretics, K-supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increase in serum potassium.

The antihypertensive effect may be potentiated by other antihypertensives.

Toxicity and a reversible increase in serum lithium concentrations have been reported during concurrent therapy with lithium preparations and ACE inhibitors. The possibility of a similar effect after the use of eprosartan

cannot be excluded and careful monitoring of serum lithium levels is recommended during concomitant use.

sec. 4.5 proposed

No effect on the pharmacokinetics of digoxin and the pharmacodynamics of warfarin or glyburide (glibenclamide) has been shown with eprosartan. Similarly no effect on eprosartan pharmacokinetics has been shown with ranitidine, ketoconazole or fluconazole.

 

Eprosartan can be used concomitantly with thiazide diuretics (e.g. hydrochlorothiazide) and calcium channel blockers (e.g. sustained-release nifedipine) without evidence of clinically significant adverse interactions.

 

Since in placebo-controlled clinical studies significantly elevated serum potassium concentration were observed, and based on experience with the use of other drugs that affect the renin-angiotensin-aldosterone system, concomitant use of K-sparing diuretics, K­supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increase in serum potassium.

The antihypertensive effect may be potentiated by other antihypertensives.

 

Toxicity and a reversible increase in serum lithium concentrations have been reported during concurrent therapy with lithium preparations and ACE inhibitors. The possibility of a similar effect after the use of eprosartan can not be excluded and careful monitoring of serum lithium levels is recommended during concomitant use.

 

Eprosartan has been shown not to inhibit human cytochrome P450 enzymes CYP1A, 2A6, 2C9/8, 2C19, 2D6, 2E, and 3A in vitro.

sec. 4.8 present

In placebo-controlled clinical trials, the overall incidence of adverse experiences reported with eprosartan was comparable to placebo. Adverse experiences have usually been mild and transient in nature and have only required discontinuation of therapy in 4.1% of patients treated with eprosartan in placebo-controlled studies (6.5% for placebo). The frequencies indicated in the text are based on the non-corrected numbers in placebo-controlled clinical trials.

In clinical trials following adverse events were reported:

 

Body as a whole

Common: viral infection, injury and pain.

 

Cardiovascular system

Common: chest pain and palpitation.

 

Gastrointestinal system

Common: Abdominal pain and dyspepsia.

 

Respiratory system

Common: Rhinitis, pharyngitis, dyspnoea, upper respiratory tract infection and coughing.

 

Nervous system

Common: headache, dizziness, fatigue and depression

 

Musculoskeletal system

Common: Back pain and arthralgia.

 

Urogenital system

Common: Urinary tract infections.

 

Metabolic system

Common: Hypertriglyceridaemia.

A relationship with eprosartan treatment could not always be established.

The following adverse events were reported by the market:

 

Body as a whole

Rare: Asthenia.

 

Nervous system

Rare: Headache and dizziness.

 

Cardiovascular system

Very rare: Hypotension, including postural hypotension

 

Skin and appendages

Rare: Skin reactions (rash, pruritis, urticaria).

Very rare: Facial swelling and/or angioedema.

 

Laboratory Findings

In placebo-controlled clinical studies, significantly elevated serum potassium concentrations were observed in 0.9% of patients treated with eprosartan and 0.3% of patients who received placebo.

Significantly low values of haemoglobin were observed in 0.1% and 0% patients treated with eprosartan and placebo respectively. In rare cases elevations of BUN values were reported in patients treated with eprosartan. In rare cases increases in liver function values were also observed but were not considered to be causally related to eprosartan treatment.

sec. 4.8 proposed

In placebo-controlled clinical trials, the overall incidence of adverse experiences reported with eprosartan was comparable to placebo. Adverse experiences have usually been mild and transient in nature and have only required discontinuation of therapy in 4.1% of patients treated with eprosartan in placebo-controlled studies (6.5% for placebo).

 

 

ADVERSE EXPERIENCES BY EPROSARTAN-TREATED PATIENTS PARTICIPATING IN CLINICAL TRIALS

 

MedDRA system organ class	Common ³1/100, <1/10	Uncommon ³1/1,000, <1/100	Rare ³1/10,000 <1/1,000	Very rare ≤1/10,000 incl. isolated reports	Unknown
Infections and infestations	Viral infection
Metabolism and nutrition disorders	Hyper- triglyceridaemia	Hyperkalaemia
Nervous system disorders	Headache, dizziness, fatigue, depression
Cardiac disorders	Chest pain, palpitation
Vascular disorders					Hypotension, including postural hypotension
Respiratory, thoracic and mediastinal disorders	Rhinitis, pharyngitis, dyspnoe, upper respiratory tract infection, cough
Skin and subcutaneous tissue disorders					Allergic skin reaction (e.g. rash, pruritus, urticaria) facial swelling, angioedema
Musculoskeletal and connective tissue disorders	Back pain, arthralgia
Renal    and urinary disorders	Urinary tract infections
Gastrointestinal disorders	Nausea, vomiting, diarrhoea, abdominal pain, unspecific gastrointestinal complaints, dyspepsia
General disorders and administration site reactions	Asthenia, injury, pain
Investigations			Haemoglobin decreased, blood urea increased

 

A relationship with eprosartan treatment could not always be established.

 

In addition to those adverse events reported during clinical trials, the following side effects have been reported spontaneously during postmarketing use of eprosartan. A frequency cannot be estimated from the available data (not known).

 

Renal and urinary disorders

Impaired renal function including renal failure in patients at risk (e.g. renal artery stenosis).

 

 

 

sec. 4.9 present

Limited data are available in regard to overdose in humans. The most likely manifestation of overdose would be hypotension. If symptomatic hypotension should occur, supportive treatment should be instituted.

sec. 4.9 proposed

Limited data are available in regard to overdose in humans. Eprosartan was well tolerated after oral dosing (maximum unit dose taken to date in humans 1200 mg). The most likely manifestation of overdose would be hypotension. If symptomatic hypotension should occur, supportive treatment should be instituted.

sec. 5.1 present

 

Pharmacotherapeutic class: Antihypertensive agent: ATC-code: C09CA02.
(...)

sec. 5.1 proposed

Pharmacotherapeutic class: Eprosartan, ATC-code: C09CA02.

(...)

sec. 5.3 present

(...) 
c) Reproduction toxicity
(...)

sec. 5.3 proposed

(...)

c) Reproductive and developmental toxicity
(...)

sec. 6.1 present

Tablet cores

Lactose monohydrate

Microcrystalline cellulose

Pregelatinised starch

Croscarmellose sodium

Magnesium stearate

 

Film-coat

Titanium dioxide

Hypromellose 3CP

Hypromellose 6CP

Macrogol 400

Polysorbate 80

Iron oxide yellow

Iron oxide red

sec. 6.1 proposed

Tablet Core:

Lactose monohydrate

Microcrystalline cellulose

Pregelatinised starch

Croscarmellose sodium

Magnesium stearate

Purified water.

 

Film-coat:

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol 400

Polysorbate 80 (E433)

Iron oxide yellow (E172)

Iron oxide red (E172).

sec. 6.5 present

Opaque PVC/Aclar blister packs or HDPE bottles with polypropylene caps.

Blister packs: 14 film-coated tablets

28 film-coated tablets

56 film-coated tablets

98 film-coated tablets

280 (10 x 28) film-coated tablets

400 mg tablets are also available in blister packs:

4 film coated tablets

7 film coated tablets

50 (5 x 10) film coated tablets

Bottle packs: 100 film coated tablets

Not all pack sizes may be marketed.

sec. 6.5 proposed

Opaque PVC/Aclar/Al blister packs or HDPE bottles with polypropylene caps.

 

Blister packs:

4 film coated tablets

7 film coated tablets

14 film-coated tablets

28 film-coated tablets

50 (5 x 10) film coated tablets

56 film-coated tablets

98 film-coated tablets

280 (10 x 28) film-coated tablets

 

Bottle packs: 100 film coated tablets

 

Not all pack sizes may be marketed.

sec. 10 present

January 2005

sec. 10 proposed

October 2007