Teveten Plus 600mg/12.5mg film-coated tablets

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 2010/18/1 2007/15/1

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 108/27/1 to PA 2007/15/1

Section 4.3     Contraindications
Addition of:
The concomitant use of Teveten Plus 600mg/12.5mg with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2)

Section 4.4    Special warnings and precautions for use
Addition of:
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.

Section 4.5    Interactions with other medicinal products
Addition of:
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).

Section 5.1    Pharmacodynamic properties
Addition of a paragraph relating to two large trials - ONTARGET and VA NEPHRON-D idscussing the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker

MAH address changed from Southampton UK to Maidenhead UK.

Section 4.5; Interaction with other medicinal products and other forms of interaction:-
The following paragraphs were changed to read:

Calcium salts & Vitamin D:

Thiazide diuretics may increase serum calcium levels due to decreased excretion.  If calcium supplements or medicinal products affecting serum calcium levels (e.g. Vitamin D therapy) must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

 

Cholestyramine and colestipol resins:

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins such as colesstyramine or colestipol.  However, the interaction might be minimised by graded intake of hydrochlorothiazide and the resin in the way that hydrochlorothiazide is taken at least 4 hours before or 4-6 hours after the resin. 

Medicinal products lowering serum sodium level:

The hyponatraemic effect of hydrochlorothiazide may be intensified by concomitant administration of drugs such as antidepressants, antipsychotics, antiepileptics, etc.  Caution is advised in long-term administration of these drugs.

Section 4.6; Fertility, Pregnancy and Lactation:-
The following paragraph was deleted......
Due to the effects on the pregnancy of each of the active substances of this medicinal product, the use of Teveten Plus 600mg/12.5mg is not recommended during the first trimester of pregnancy (see section 4.4).  The use of Teveten Plus 600mg/12.5mg is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

....and replaced with:
Angiotensin II Receptor Blocker (AIIRAs):

The use of eprosartan is not recommended during the first trimester of pregnancy (see section 4.4).  The use of eprosartan is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

The following paragraph was changed to read:
Hydrochlorothiazide:

There is limited experience with hydrochlorothiazide during pregnancy especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placental.  Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimesters may compromise the foetoplacental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion without beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situation where no other treatment could be used. 

The following paragraph was added:
Fertility:

There are no clinical data on fertility.

Nonclinical data on eprosartan did not reveal any effects on male and female fertility.  No preclinical information on possible effects of hydrochlorothiazide on fertility is available.


Section 4.8; Undesirable Effects:-
The following paragraph was added:

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.  It allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.  Website: www.hpra.ie; e-mail: medsafety@hpra.ie

This variation concerned the following changes:
- Update of SPC sections 2, 4.2, 4.3, 4.4, 4.5, 4.6, 4.8, 4.9 & 6.4 in line with the Eprosartan EU Core Safety Profile (CSP)

Section 3: Addition of text "and no incription on the other side"



The Solvay embossing has been removed from the tablet.  Highlighted text is now deleted

 

3.       PHARMACEUTICAL FORM

 

 

The inscription of the tablet is “5147” on one side. and “SOLVAY” on the other side.

 

 

A new foil composition has been added to Section 6.5.  The description of the original foil has been amended.  The composition of this original foil remains unchanged. Amended or deleted text is highlighted.

 

6.5     Nature and contents of container

 

White PVC/PCTFE/Aluminium foil blisters or white PVC/PVDC/Aluminium foil blisters

 

 

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.

The source of excipient pregelatinised starch is included.

Each film-coated tablet contains 600 mg eprosartan (as mesylate) and 12.5 mg hydrochlorothiazide.

For full list of excipients, see section 6.1.

 

3.  PHARMACEUTICAL FORM

Film-coated tablet

Butterscotch-coloured, capsule-shaped film-coated tablet

The inscription of the tablet is 5147 on one side and SOLVAY on the other side.

 

4.2  Posology and method of administration

The recommended dose is one tablet Teveten Plus 600 mg/12.5 mg once daily, which should be taken

in the morning. The switch from eprosartan monotherapy to the fixed combination can be considered

after 8 weeks of blood pressure stabilization. Teveten Plus 600 mg/12.5 mg can be taken with or

without food.

 

The use of Teveten Plus in patients with mild to moderate hepatic impairment is not recommended

since there is currently only limited experience of eprosartan mesylate in this patient group. In patients

with severe hepatic impairment Teveten Plus is contraindicated (see sections 4.3 and 4.4).

 

Renal Impairment

In patients with mild to moderate renal impairment (creatinine clearance ¡Ý 30 ml/min) dose adjustment

is not necessary. Teveten Plus is contraindicated in patients with severe renal impairment (see sections

4.3 and 4.4).

 

4.3 Contraindications

History of hypersensitivity to eprosartan, sulphonamide-derived substances (as hydrochlorothiazide)

or to any of the excipients.

Second and third trimester of pregnancy (see section 4.6).

Lactation.

Severe hepatic impairment.

Severe renal impairment (creatinine clearance < 30 ml/min)

Therapy resistant hypokalaemia or hypercalcaemia

Cholestasis and biliary obstructive disorders

Refractory hyponatraemia

Symptomatic hyperuricaemia/gout

 

4.4    Special warnings and special precautions for use

 

Eprosartan

 

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.

Cautious administration and adequate monitoring of serum potassium and acid-base-balance in

patients at risk for development of hyperkalaemia: patients with renal impairment, diabetes mellitus,

concomitant administration of potassium-sparing diuretics, potassium supplements or potassiumcontaining

salt substitutes, or other medicinal products which may lead to an increase of serum

potassium (see section 4.5) is recommended.

 

Eprosartan/Hydrochlorothiazide combination

 

As with other medicinal products containing angiotensin II antagonists and thiazide in combination,

the coadministration of Teveten Plus and lithium is not recommended (see section 4.5).

 

Hepatic impairment

Teveten Plus is contraindicated in severe hepatic impairment (see section 4.3).

 

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

 

4.5    Interaction with other medicinal products and other forms of interaction

 

Potential interactions related to both eprosartan and hydrochlorothiazide:

Concomitant use not recommended

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during

concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with

angiotensin II antagonists. In addition, renal clearance of lithium is reduced by thiazides and

consequently the risk of lithium toxicity may be increased. Therefore use of Teveten Plus and lithium

in combination is not recommended (see section 4.4). If use of the combination proves necessary,

careful monitoring of serum lithium levels is recommended.

 

Concomitant use requiring caution 

Baclofen:

Potentiation of antihypertensive effect may occur.

 

Non-steroidal anti-inflammatory medicinal products:

NSAIDs (ie acetylsalicylic acid (> 3 g/day), COX-2 inhibitors and non-selective NSAIDs) may reduce

the antihypertensive effect of thiazide diuretics and angiotensin II antagonists.

In some patients with compromised renal function (eg dehydrated patients or elderly patients with

compromised renal function) the co-administration of angiotensin II antagonists and agents that inhibit

cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal

failure, which is usually reversible. Therefore, the combination should be administered with caution,

especially in the elderly. Patients should be adequately hydrated and consideration should be given to

monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

 

Concomitant use to be taken into account

Amifostine:

Potentiation of antihypertensive effect may occur.

 

Other antihypertensive agents:  

The blood pressure lowering effect of Teveten Plus can be increased by concomitant use of other

antihypertensive medicinal products.

 

Alcohol, barbiturates, narcotics or antidepressants:

Potentiation of orthostatic hypotension may occur.

 

Potential interactions related to eprosartan:

 

Concomitant use not recommended

Medicinal products affecting potassium levels:

Based on experience with the use of other medicinal products that affect the renin-angiotensin system,

concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing

potassium or other medicinal products that may increase serum potassium levels (eg heparin, ACE

inhibitors) may lead to increases in serum potassium. If medicinal product which affect potassium

levels are to be prescribed in combination with Teveten Plus, monitoring of potassium plasma levels is

advised (see section 4.4).

 

Potential interactions related to hydrochlorothiazide:

 

Concomitant use not recommended

Medicinal products affecting potassium levels:  

The potassium-depleting effect of hydrochlorothiazide may be potentiated by the coadministration of

other medicinal products associated with potassium loss and hypokalaemia (eg other kaliuretic

diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium or

salicylic acid derivatives). Such concomitant use is therefore not recommended (see section 4.4).

 

Concomitant use requiring caution

Calcium salts:

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium

supplements must be prescribed, serum calcium levels should be monitored and calcium dosage

adjusted accordingly.

 

Cholestyramine and colestipol resins:

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.

 

Digitalis glycosides:

Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-induced

cardiac arrhythmias.

 

Medicinal products affected by serum potassium disturbances:

Periodic monitoring of serum potassium and ECG is recommended when Teveten Plus is administered

with medicinal products affected by serum potassium disturbances (eg digitalis glycosides and

antiarrhythmics) and with the following torsades de pointes (ventricular tachycardia)-inducing

medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to

torsades de pointes (ventricular tachycardia):

¡¤          Class Ia antiarrythmics (eg quinidine, hydroquinidine, disopyramide).

¡¤          Class III antiarrythmics (eg amiodarone, sotalol, dofetilide, ibutilide).

¡¤          Some antipsychotics (eg thioridazine, chlorpromazine, levomepromazine, trifluoperazine,

        cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

¡¤          Others (eg bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine,

        terfenadine, vincamine IV).

 

Non-depolarizing skeletal muscle relaxants (eg tubocurarine):

The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

 

Anticholinergic agents (eg atropine, biperiden):

Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and

stomach emptying rate.

 

Antidiabetic medicinal products (oral agents and insulin):

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the

antidiabetic medicinal product may be required (see section 4.4).

 

Metformin:

Metformin should be used with caution because of the risk of lactic acidosis induced by possible

functional renal failure linked to hydrochlorothiazide.

 

Beta-blockers and diazoxide: 

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

 

Pressor amines (eg noradrenaline):

The effect of pressor amines may be decreased.

 

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol):

Dosage adjustment of uricosuric medicinal products may be necessary since hydrochlorothiazide may

raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be

necessary. Coadministration of a thiazide may increase the incidence of hypersensitivity reactions to

allopurinol.

 

Amantadine:

Thiazides may increase the risk of adverse effects caused by amantadine.

 

Cytotoxic agents (eg cyclophosphamide, methotrexate):

Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their

myelosuppressive effects.

 

Tetracyclines: 

Concomitant administration of tetracyclines and thiazides increases the risk of tetracycline-induced

increase in urea. This interaction is probably not applicable to doxycycline.

 

4.6  Pregnancy and lactation

Pregnancy:

As a precaution Teveten Plus should not be used during the first trimester of pregnancy. A change to a

suitable alternative treatment should occur before a planned pregnancy. If pregnancy is determined,

Teveten Plus must be discontinued as soon as possible.

There is no experience on the use of Teveten Plus in pregnant women. Animal studies of the

combination eprosartan/hydrochlorothiazide did not indicate a teratogenic effect; however, eprosartan

did show fetotoxicity (see section 5.3).

The use of Teveten Plus is contraindicated during the second and third trimesters of pregnancy. (see

section 4.3 contraindications).

During the second and third trimester of pregnancy, substances that act on the renin-angiotensin

system may cause damage (hypotension, impairment of renal function, oliguria and/or anuria,

oligohydramnia, cranial hypoplasia, intrauterine growth retardation) and death in foetuses and

neonates. Cases of pulmonary hypoplasia, facial anomalies and contractions of limbs were also

reported.

 

Thiazides cross the placental barrier and appear in umbilical cord blood. They may cause foetal

electrolyte disturbances and possibly other reactions which have occurred in adults. Cases of neonatal

thrombocytopenia, foetal or neonatal jaundice have been reported after maternal thiazide therapy. If

pregnancy is detected during treatment, Teveten Plus 600 mg/12.5 mg should be discontinued as soon

as possible and skull and renal function should be checked with echography if, inadvertently, the

treatment was taken for a long period. (see 4.3 Contraindications).

 

Lactation:

It is not known whether eprosartan is excreted in human milk. Significant levels of eprosartan were

shown to be present in rat milk.

Hydrochlorothiazide is excreted into human milk. Because of the potential for adverse effects on the

nursing infant, Teveten Plus is contraindicated during lactation (see section 4.3). A decision should be

made whether to discontinue breast-feeding or discontinue the drug, taking into account the

importance of the drug to the mother.

 

5.1 Pharmacodynamic properties

 

Pharmacotherapeutic group: Angiotensin II antagonists and diuretics: ATC-code: C09DA02.

 

Teveten Plus 600 mg/12.5 mg

In a placebo-controlled, 8 weeks clinical trial in 473 patients with essential hypertension it was shown

that the combination of 600 mg eprosartan and 12.5 mg hydrochlorothiazide is well tolerated and

efficacious. Teveten Plus 600 mg/12.5 mg reduced systolic and diastolic blood pressure to a clinically

relevant degree and was statistically significant superior to both individual components and placebo,

despite a high placebo response (p=0.08 for comparison of eprosartan alone and placebo). Tolerability

was equal for both eprosartan/hydrochlorothiazide 600 mg/12.5 mg, eprosartan and placebo.

 

In another clinical trial patients with a diastolic blood pressure between 98 and 114 mmHg, who were

not treated sufficiently with a 3-weeks treatment of eprosartan 600 mg alone, were given either

eprosartan/hydrochlorothiazde 600 mg/12.5 mg or 600 mg eprosartan alone for 8 weeks. The

combination caused a statistically significant and clinically relevant additional decrease in systolic and

diastolic blood pressure in patients not reacting sufficiently to eprosartan monotherapy. Tolerability

was equally satisfactory for both the combination and monotherapy.

 

5.2    Pharmacokinetic properties

 

Eprosartan

Absolute bioavailability following oral administration of eprosartan is approx. 13%. Eprosartan

plasma concentrations peak at 1 to 2 hours after dosing in the fasted state. The terminal elimination

half-life of eprosartan is typically 5 to 9 hours. A slight accumulation (14 %) is seen with chronic use

of eprosartan. Administration of eprosartan with food delays absorption, but does not decrease the

bioavailability.

In the dose range between 100 to 800 mg there is a slight less than dose-proportional increase in

exposure to eprosartan, most likely due to the physicochemical properties of the drug.

 

5.3  Preclinical safety data

 

The toxicologic target organ was the kidney. The combination eprosartan/hydrochlorothiazide induced

functional renal changes (increases in serum urea and in serum creatinine). Furthermore, tubular de-and

regeneration in the kidneys were induced at higher doses in mice and dogs, probably by way of

altered renal haemodynamics (reduced renal perfusion as a consequence of hypotension leading to

tubular hypoxia with tubular cellular degeneration).

 

6.1    List of excipients

 

Tablet core:

lactose monohydrate

microcrystalline cellulose

pregelatinised starch (from maize)

crospovidone

magnesium stearate

Purified water

 

Film coat:

 

10.  DATE OF REVISION OF THE TEXT

 

June 2007