Essential hypertension. Teveten Plus HCT 600 mg/12.5 mg is indicated in patients whose
blood pressure cannot be treated adequately with eprosartan alone.

Posology
The recommended dose is one film-coated tablet of Teveten Plus HCT 600 mg/12.5 mg
once daily, which should be taken in the morning. A change from eprosartan monotherapy
to the fixed combination can be considered after 8 weeks of blood pressure stabilisation.
Elderly patients
The dosage does not have to be adjusted in elderly patients. However, only limited
information is available for this age group.
Children and adolescents
As its efficacy and harmlessness in use with children have not been proven, treatment of
children and young people under 18 with Teveten Plus HCT 600 mg/12.5 mg is not
recommended.
Liver function disorders
The use of Teveten Plus HCT 600 mg/12.5 mg in patients with mild to moderate liver
function disorder is not recommended, since at present there is only limited experience
with eprosartan mesylate in this patient group. In patients with severe liver function
disorder Teveten Plus HCT 600 mg/12.5 mg is contraindicated (see also sections 4.3 and
4.4.).

Renal function disorders
In patients with mild to moderate renal function disorders (creatinine clearance ≥ 30
ml/min), no dosage adjustment is necessary. In patients with severe renal function
disorders, Teveten Plus HCT 600 mg/12.5 mg is contraindicated (see also sections 4.3 and
4.4).
Method of administration
Teveten Plus HCT 600 mg/12.5 mg can be taken with or without food.

Hypersensitivity to the active substance, sulfonamide derivatives (such as hydrochlorothiazide) or any of the other ingredients listed in section 6.1 • Second and third trimester of pregnancy (see sections 4.4 and 4.6) • Severe hepatic impairment • Cholestasis and bile duct obstructions • Severe renal impairment (creatinine clearance < 30 ml/min) • Haemodynamically significant bilateral renal artery disease or severe stenosis in a single functioning kidney • Treatment-resistant hypokalaemia or hypercalcaemia • Refractory hyponatraemia • Symptomatic hyperuricaemia/gout • The concomitant use of Teveten Plus HCT 600 mg/12.5 mg with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or restricted renal function (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

Hypersensitivity reactions to hydrochlorothiazide are more likely to occur in patients with
known allergies, including hypersensitivity to sulfonamide derivatives.
Patients at risk of renal impairment
In patients whose renal function is dependent on the continued intrinsic activity of the
renin-angiotensin-aldosterone system (e.g. patients with severe cardiac insufficiency
[NYHA classification: class IV], bilateral renal artery stenosis or renal artery stenosis in a
single functioning kidney), under treatment with ACE inhibitors there is a risk of oliguria
and/or progressive azotaemia developing and in rare cases acute renal failure. The
likelihood of such events is higher in patients treated concomitantly with a diuretic. There
is insufficient therapeutic experience with angiotensin II receptor (type AT1) antagonists
such as eprosartan to state whether there is a similar risk of renal impairment developing
in patients who are susceptible to this. Since in such patients there is an increased risk of a
severe drop in blood pressure and renal insufficiency, renal function should be monitored
closely.
Renal function disorders and kidney transplant
If eprosartan plus hydrochlorothiazide is used in patients with renal function disorders,
before starting and at regular intervals during the treatment with eprosartan plus
hydrochlorothiazide, the renal function, serum potassium and uric acid levels should be
determined. If renal function worsens under the treatment with eprosartan plus
hydrochlorothiazide, this should be reconsidered (see section 4.3). If renal function
disorders exist, hydrochlorothiazide-associated azotaemia can occur.
No experiences with the use of Teveten Plus HCT 600 mg/12.5 mg in kidney transplant
patients are available.

Liver function disorders
In patients with mild to moderate liver function disorders, eprosartan should be used with
special care, as only limited experience is available with this patient population.
Hydrochlorothiazide should be used only with caution in patients with mild to moderate
liver function disorder, as it can trigger intrahepatic cholestasis. Changes in the fluid and
electrolyte balance can cause a hepatic coma.
Metabolic and endocrine disorders
Hydrochlorothiazide can affect glucose tolerance and necessitate a dose adjustment of
antidiabetics. Latent diabetes mellitus can become manifest during treatment with Teveten
Plus HCT 600 mg/12.5 mg. At a dosage of 12.5 mg hydrochlorothiazide in Teveten Plus
HCT 600 mg/12.5 mg, only mild metabolic and endocrine side effects have been observed
(increase in cholesterol and triglycerides).
Electrolyte imbalance
Hydrochlorothiazide can cause fluid and electrolyte imbalance (hypokalaemia,
hyponatraemia, hypercalcaemia, hypomagnesaemia and hypochloraemic alkalosis).
As with all patients treated with diuretics, the electrolyte imbalance should be monitored
regularly. Potassium-sparing diuretics, potassium supplements, potassium-containing salt
substitutes or medicinal products that may increase potassium levels (e.g. those containing
trimethoprim) may elevate serum potassium levels and should therefore only be used with
caution in combination with eprosartan (see section 4.5).
Choroidal effusion, acute myopia and secondary narrow-angle glaucoma
Hydrochlorothiazide, a sulfonamide, can cause a specific reaction resulting in choroidal
effusion with visual field defect, temporary acute myopia and acute narrow-angle
glaucoma. The symptoms occur typically within hours to weeks after the start of therapy
and include a sudden reduction in visual acuity or eye pain. Untreated narrow-angle
glaucoma can lead to permanent vision loss. As a first measure, hydrochlorothiazide
should be discontinued as soon as possible. In the case of continuing uncontrollable
intraocular pressure, immediate medical or surgical treatment should be considered.
Risk factors for the development of acute narrow-angle glaucoma can include a known
allergy to sulfonamides or penicillin.
Hypotension
Symptomatic hypotension can occur in patients with severe sodium- or volume depletion,
caused for example through high-dose diuretic therapy, a low-salt diet, diarrhoea or
vomiting. Sodium- and/or volume depletion should be corrected before treatment with
Teveten Plus HCT 600 mg/12.5 mg.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As also in the case of treatment with other vasodilators, caution is advisable in patients
with aortic and mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism do not respond adequately to antihypertensives
whose action is based on inhibition of the renin-angiotensin-aldosterone system. Therefore
use of Teveten Plus HCT 600 mg/12.5 mg is not recommended.
Coronary heart disease
There is only limited experience in patients with coronary heart disease.
Pregnancy
Treatment with Angiotensin II receptor (type AT1) antagonists (AIIRAs) should not be
started during pregnancy. Patients wishing to become pregnant should change to an alternative blood pressure-lowering treatment with a suitable safety profile for use in
pregnancy, unless continuation of the treatment with AIIRAs is absolutely necessary. If
pregnancy is diagnosed, the treatment with AIIRAs should be ended immediately and, if
necessary, an alternative therapy should be started (see sections 4.3 and 4.6).
Non-melanocytic skin cancer
Two epidemiological studies included in the Danish National Cancer Register have
observed an increased risk of non-melanocytic skin cancer (NMSC), [basal cell carcinoma
(BCC) and squamous cell carcinoma (SCC)] with an increasing cumulative dose of
hydrochlorothiazide (HCTZ).
The photosensitising effects of HCTZ could contribute to the appearance of NMSC.
Patients receiving HCTZ should be informed of the risk of NMSC and advised to check
their skin regularly for new lesions and report any suspicious skin changes immediately.
Potential preventive measures should be recommended to patients in order to minimise the
risk of skin cancer, e.g. limited exposure to sunlight and UV rays, or the use of appropriate
sun protection in the event of exposure. Suspicious skin changes should be investigated
immediately and include the histological examination of biopsies, if necessary. The use of
HCTZ should be tested in patients previously diagnosed with NMSC (see also section
4.8).
Acute respiratory tract toxicity
Severe, albeit very rare cases of acute respiratory toxicity, including acute respiratory
distress syndrome (ARDS), have been reported following the administration of
hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after
taking hydrochlorothiazide. Symptoms at onset include dyspnoea, fever, a deterioration in
lung function and hypotension. If ARDS is suspected, Teveten Plus HCT 600 mg/12.5 mg
should be discontinued and appropriate treatment initiated. Hydrochlorothiazide must not
be used in patients who have previously experienced ARDS after taking
hydrochlorothiazide.
Other warnings and precautionary measures
It has been reported that thiazide diuretics lead to a worsening or activation of systemic
lupus erythematosus.
Hydrochlorothiazide can lead to a positive result in doping tests.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor
antagonists or aliskiren increase the risk of hypotension, hyperkalaemia and a reduction in
renal function (including acute renal failure). Dual blockade of the RAAS by the
concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not
therefore recommended (see sections 4.5 and 5.1).
If treatment with dual blockade is considered absolutely necessary, this should only be
carried out under the supervision of a specialist and with close monitoring of renal
function, electrolyte values and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly
in patients with diabetic nephropathy.
Lactose warning
Patients with rare hereditary galactose intolerance, total lactase deficiency or glucosegalactose
malabsorption should not take Teveten Plus HCT 600 mg/12.5 mg.

 

Potential interactions related to both eprosartan and hydrochlorothiazide:Concomitant use of the following medicinal product is not recommended:
Lithium:
When lithium has been administered concomitantly with angiotensin converting enzyme
(ACE) inhibitors and - rarely - angiotensin II receptor (type AT1) antagonists, a reversible
increase in the serum lithium concentration and toxicity has been reported. In addition,
renal clearance of lithium is reduced by thiazide diuretics and as a result the risk of
lithium toxicity possibly increases. For this reason, concomitant use of Teveten Plus HCT
600 mg/12.5 mg and lithium is not recommended (see section 4.4). However, if such a
combination should prove necessary, the serum lithium level should be monitored
carefully.
Caution is advisable with concomitant use of the following medicinal products:
Baclofen:
The antihypertensive effect can intensify.
Non-steroidal anti-inflammatories (NSAIDs):
As with ACE inhibitors, concomitant use of angiotensin II receptor (type AT1)
antagonists and NSAIDs can increase the risk of deterioration in renal function, including
possible acute kidney failure, and an increase in the serum potassium level, particularly in
patients with already impaired renal function. Caution is advised with combined
administration, particularly in elderly patients. Attention should be paid to maintaining an
adequate fluid balance in patients and monitoring of renal function should be considered
after introduction of the combination therapy and at regular intervals during the rest of the
therapy.
The combined use of losartan and the NSAID indomethacin has led to reduced
effectiveness of the angiotensin II receptor (type AT1) antagonists; a class effect cannot
be excluded.
The following should be taken into consideration when the following medicinal
products are used concomitantly:
Amifostine:
The antihypertensive effect can be intensified.
Other antihypertensives:
The blood pressure-lowering action of Teveten Plus HCT 600 mg/12.5 mg can be
intensified through concomitant use of other antihypertensives.
Alcohol, barbiturates, narcotics or antidepressants:
Orthostatic hypotension can intensify.
Possible interactions connected with eprosartan
Concomitant use of the following medicinal products is not recommended:
Medicinal products that affect the potassium level:
Based on the experiences with other medicinal products that affect the renin-angiotensin
system, concomitant administration of potassium-sparing diuretics, potassium
supplements, potassium-containing salt substitutes or other medicinal products that can
increase the serum potassium level (e.g. heparin, medicinal products containing
trimethoprim, ACE inhibitors) can lead to an increase in the serum potassium level. If a
concomitant prescription of medicinal products that can affect the serum potassium level and Teveten Plus HCT 600 mg/12.5 mg is necessary, monitoring of the serum potassium
level is recommended (see section 4.4).
Data from clinical trials have shown that dual blockade of the renin angiotensin
aldosterone system (RAAS) due to concomitant use of ACE inhibitors, angiotensin II
receptor antagonists or aliskiren compared with the use of a single substance acting on the
RAAS is accompanied by a higher rate of unwanted events such as hypotension,
hyperkalaemia and a reduction in renal function (including acute renal failure) (see
sections 4.3, 4.4 and 5.1).
Possible interactions connected with hydrochlorothiazide
Concomitant use of the following medicinal products is not recommended:
Medicinal products that affect the potassium level:
The potassium-reducing effect of hydrochlorothiazide can be intensified through
concomitant administration of other medicinal products associated with potassium loss
and hypokalaemia (such as, for example, other kaliuretic diuretics, laxatives,
corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G (sodium) or salicylic
acid derivatives). For this reason, concomitant use is not recommended (see section 4.4).
Caution is advisable with concomitant use of the following medicinal products:
Calcium salts and vitamin D:
Thiazide diuretics can lead to an increase in the serum calcium level because of reduced
excretion. If a concomitant prescription of calcium or calcium salt preparations (such as
for example vitamin D therapy) is necessary, the serum calcium level should be monitored
and the dose of the calcium preparation should be adjusted accordingly.
Cholestyramine and colestipol:
Absorption of hydrochlorothiazide is impaired in the presence of anion exchange resins.
The interaction may however possibly be reduced by the staggered taking of
hydrochlorothiazide and anion exchange resin if hydrochlorothiazide is taken for at least 4
hours before or 4-6 hours after taking the anion exchange resin.
Cardiac glycosides:
Thiazide-induced hypokalaemia or hypomagnesaemia can promote the occurrence of
digitalis-related arrhythmia.
Medicinal products that are affected by disorders of the serum potassium level:
Regular checks on serum potassium levels and ECGs are recommended, if Teveten Plus
HCT 600 mg/12.5 mg is given together with medicinal products whose action is affected
by disorders of the serum potassium level (e.g. cardiac glycosides and antiarrhythmics),
and also with the following medicinal products which can cause torsades de pointes
(ventricular tachycardia) (including some antiarrhythmics), where hypokalaemia is a
predisposing factor for the occurrence of torsades de pointes (ventricular tachycardia):
• Class IA antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide)
• Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)
• Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine,
trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide,
haloperidol, droperidol)
• Other (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine,
pentamidine, terfenadine, vincamine IV)
Non-depolarising muscle relaxants (e.g. tubocurarine):
The effect of non-depolarising muscle relaxants can be intensified by hydrochlorothiazide.

Anticholinergics (e.g. atropine, biperiden):
The bioavailability of thiazide diuretics can be increased through a reduction in
gastrointestinal motility and slowing down of stomach emptying.
Antidiabetics (oral antidiabetics and insulin):
Treatment with a thiazide diuretic can affect glucose tolerance. A dose adjustment of the
antidiabetic may be necessary (see section 4.4).
Metformin:
Metformin should be used only with caution. There is the risk of lactic acidosis because of
possible functional kidney failure through hydrochlorothiazide.
Beta blockers and diazoxide:
The hyperglycaemic effect of beta blockers and diazoxide can be intensified by thiazide
diuretics.
Sympathomimetics (e.g. noradrenalin):
The effect of sympathomimetics could be weakened.
Gout therapeutics (e.g. probenecid, sulfinpyrazone, allopurinol):
As hydrochlorothiazide can increase the uric acid level in the serum, a dose adjustment of
uricosurics might be necessary. An increased dose might be necessary for probenecid and
sulfinpyrazone. In the combination with thiazide diuretics, there might be an increase in
hypersensitivity reactions to allopurinol.
Amantadine:
Thiazide diuretics can increase the risk of side effects of amantadine.
Cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate):
Thiazide diuretics can reduce renal excretion of cytotoxic medicinal products and
intensify their myelosuppressive effect.
Tetracyclines:
Concomitant administration of tetracyclines and thiazide diuretics increases the
tetracycline-induced risk of increased urea. This interaction is probably not transferable to
doxycycline.
Medicinal products that reduce the serum sodium level:
The hyponatraemic action of hydrochlorothiazide may be intensified by the concomitant
administration of medicinal products such as for example antidepressants, antipsychotics,
antiepileptics etc. Caution is advised in case of long-term administration of these
medicinal products.

Pregnancy
Angiotensin II receptor (type AT1) antagonists (AIIRAs)
The use of AIIRAs during the first trimester is not recommended (see section 4.4). The
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see
sections 4.3 and 4.4).
There are no conclusive epidemiological data regarding a teratogenous risk after using
ACE inhibitors during the first trimester of pregnancy; however, a slightly increased risk
cannot be excluded. Although there are no controlled epidemiological data on the risk
with angiotensin II receptor (type AT1) antagonists (AIIRAs), there might be comparable
risks for this class of medicinal products. If continuation of the therapy with AIIRAs is not considered necessary, patients who plan a pregnancy should be changed to an alternative
antihypertensive therapy with a suitable safety profile for pregnant women. If pregnancy
is diagnosed, treatment with AIIRAs should be stopped immediately and, if necessary, an
alternative therapy started.
It is known that therapy with AIIRAs during the second and third trimesters of pregnancy
has foetotoxic effects (reduced renal function, oligohydramnios, skull ossification
retardation) and neonatal-toxic effects (renal failure, hypotension, hyperkalaemia) (see
also section 5.3). If there has been exposure to AIIRAs after the second trimester of
pregnancy, an ultrasound check of renal function and the skull is advised.
Neonates whose mothers have taken AIIRAs, should be monitored frequently and
repeatedly for hypotension (see also sections 4.3 and 4.4).
Hydrochlorothiazide
There is only limited experience with the use of hydrochlorothiazide in pregnancy,
particularly during the first trimester. Results from animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Because of the pharmacological action
mechanism of hydrochlorothiazide, use during the second and third trimesters can
compromise foetoplacental perfusion and may cause foetal and neonatal effects such as
jaundice, electrolyte disturbances and thrombocytopenia.
Because of the risk of plasma volume reduction and placental hypoperfusion, without any
benefits during the course of the disease, hydrochlorothiazide should not be used for
gestational oedema, hypertension in pregnancy or pre-eclampsia.
In the case of essential hypertension in pregnant women, hydrochlorothiazide should be
used only in rare cases in which no other treatment is possible.
Lactation
Angiotensin II receptor (type AT1) antagonists (AIIRAs)
Because no information is available regarding the use of Teveten Plus HCT 600 mg/12.5
mg during lactation, Teveten Plus HCT 600 mg/12.5 mg is not recommended. An
alternative antihypertensive therapy with a more suitable safety profile during use in
lactation is preferable, especially when nursing a new-born or pre-term infant.
Hydrochlorothiazide
Hydrochlorothiazide passes in small quantities into breast milk. Thiazide diuretics, used in
high doses for intensive diuresis, can inhibit lactation. The use of Teveten Plus HCT
mg/12.5 mg during lactation is not recommended. If Teveten Plus HCT 600 mg/12.5 mg is
used during lactation, the dose should be as low as possible.
Fertility
There are no clinical data available on fertility. Non-clinical data for eprosartan showed no
effects on female and male fertility. There is no preclinical information available on
possible effects of hydrochlorothiazide on fertility.

No studies on the ability to drive and use machines have been performed, but based on its
pharmacodynamic properties Teveten Plus HCT 600 mg/12.5 mg is unlikely to affect this
ability. When driving vehicles or operating machines, it should be taken into account that
occasionally dizziness or fatigue may occur during treatment of hypertension.

a) Summary of safety profile
The most commonly reported undesirable drug effects in patients treated with eprosartan
plus hydrochlorothiazide are headache and non-specific gastrointestinal complaints occurring in approximately 11% and 8% of patients (compared with 14% and 8% with
placebo).
b) Summary of undesirable effects
The following overview summarises the undesirable effects observed in placebocontrolled
clinical studies or reported in the scientific literature. Data on eprosartan, the
combination eprosartan plus hydrochlorothiazide and hydrochlorothiazide alone are listed
under each frequency heading (see footnotes to the table).

UNDESIRABLE EFFECTS FROM PLACEBO-CONTROLLED CLINICAL STUDIES
AND THE SCIENTIFIC LITERATURE

 

 

MedDRA system organ class	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	Unknown (cannot be estimated from available data)
Blood & lymphatic system disorders			Leukopenia		Haemolytic anaemia*	Agranulocytosis Aplastic anaemia Thrombocytopenia
Immune system disorders			Hypersensitivity			Anaphylactic reactions
Metabolism and nutrition disorders		Hyperglycaemia	Hypokalaemia Hyponatraemia Hypochloraemia Hyperuricaemia Gout Hypercholesterolaemia			Hypercalcaemia Hypomagnesaemia Hypertriglyceridaemia Anorexia
Psychiatric disorders			Depression Anxiety Insomnia Nervousness Libido disorder			Restlessness
Nervous system disorders	Headache**	Dizziness Paraesthesia
Eye disorders						Acute myopia and secondary angleclosure glaucoma* Choroidal effusion
Ear and labyrinth disorders			Vertigo**
Vascular disorders		Hypotension (e.g. orthostatic)				Vasculitis
Respiratory disorders		Rhinitis		Pulmonary oedema* Pneumonitis*	Acute respiratory distress syndrome (ARDS)5
Gastrointestinal disorders		Unspecific gastrointestinal complaints (e.g. nausea, diarrhoea, vomiting)	Constipation**	Pancreatitis*
Hepatobiliary disorders						Jaundice (intrahepatic cholestatic jaundice)
Skin and subcutaneous tissue disorders		Allergic skin reactions (e.g. rash, pruritus)	Angioedema			Toxic epidermal necrolyis Photosensitivity Cutaneous lupus erythematosus
Musculoskeletal and connective tissue disorders			Muscle cramps2**			Systemic lupus erythematosus Arthralgia
Renal and urinary disorders						Interstitial nephritis Renal failure/ impaired renal function in patients at risk (e.g. renal artery stenosis)
Reproductive system/breast disorders			Sexual dysfunction
General disorders and administration site reactions		Asthenia	Fever
Neoplasms benign, malignant and unspecified (incl cysts and polyps)						Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma)***

* Frequency based on data from the hydrochlorothiazide scientific literature
** Did not occur in a higher frequency than in placebo
*** Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ
and NMSC has been observed (see also sections 4.4 and 5.1).

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.

To report any side effect(s):

-National Pharmacovigilance Center (NPC)

o Fax: +966-11-205-7662

o SFDA Call Center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

Only limited data are available on overdose. There are individual post-marketing case
reports where doses of up to 12,000 mg eprosartan were taken. Although in most patients
no symptoms were observed, it should be mentioned that one person suffered circulatory
collapse after taking 12,000 mg eprosartan. The person recovered completely. In the case
of eprosartan plus hydrochlorothiazide, the highest dose taken was 3,600 mg
eprosartan/75 mg hydrochlorothiazide in a suicide attempt. The most likely sign of an
overdose might be hypotension. Other symptoms can be related to dehydration and electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and are most likely
to present as nausea and somnolence. Treatment should be symptomatic and supportive.
Eprosartan is not eliminated by haemodialysis. The degree to which hydrochlorothiazide
is eliminated by haemodialysis is not known.

Pharmacotherapeutic group: eprosartan and diuretics,
ATC code: C09DA02
Eprosartan
Eprosartan is a non-peptide, orally active, non-biphenyl tetrazole angiotensin II receptor
(type AT1) antagonist, which binds selectively to the AT1 receptor.
Angiotensin II plays an important role in the pathophysiology of hypertension. It is the
most important hormone of the renin-angiotensin-aldosterone system and has a
vasoconstrictive action.
Eprosartan antagonises the effect of angiotensin II on blood pressure, renal blood flow and
aldosterone secretion in test subjects. Blood pressure control is maintained over a 24-hour
period with no first dose orthostatic dysregulation or reflex tachycardia. Discontinuation
of treatment with eprosartan does not lead to a rapid rebound increase in blood pressure.
Eprosartan does not compromise renal autoregulatory mechanisms. In healthy adult males,
eprosartan has been shown to increase mean effective plasma flow.
Eprosartan does not potentiate effects caused by bradykinin (ACE-mediated), e.g. cough.
Hydrochlorothiazide
Hydrochlorothiazide is a well-documented thiazide diuretic. Thiazide diuretics affect the
renal-tubular mechanism of electrolyte absorption and increase the excretion of fluid,
sodium and chloride. The diuretic action of hydrochlorothiazide reduces plasma volume,
increases plasma renin activity and increases aldosterone secretion, with a consequent
increase in potassium excretion connected with bicarbonate loss and a decrease in the
serum potassium levels. The antihypertensive action of hydrochlorothiazide appears to be
due to combined diuretic and direct vascular activity (reduction of vascular resistance).
Non-melanocytic skin cancer: based on current data from epidemiological studies, a
cumulative, dose-dependent relationship was observed between HCTZ and NMSC. One
study included a cohort of 71,533 cases of BCC and 8,629 cases of SCC with control
groups of 1,430,833 and 172,462 individuals, respectively. A high dosage of HCTZ (>
50,000 mg, cumulative) was associated with an adjusted odds ratio of 1.29 (95%
confidence interval: 1.23 – 1.35) for BCC and 3.98 (95% confidence interval: 3.68 – 4.31)
for SCC. A substantial cumulative dose-effect relationship was established with both BCC
and SCC. Another study revealed a potential relationship between lip cancer (SCC) and
HCTZ exposure: 633 cases of lip cancer were compared to a control group comprising
63,067 individuals using a risk-oriented sampling procedure. A cumulative dose-effect
relationship with an adjusted odds ratio of 2.1 (95% confidence interval: 1.7 – 2.6) was
established, increasing to an odds ratio of 3.9 (3.0-4.9) on greater exposure (~ 25,000 mg)
and to an odds ratio of 7.7 (5.7 – 10.5) on administration of the highest cumulative dose (~
100,000 mg) (see also section 4.4).
Teveten Plus HCT 600 mg/12.5 mg
In a placebo-controlled, 8-week clinical study on 473 patients with essential hypertension,
the combination of 600 mg eprosartan and 12.5 mg hydrochlorothiazide proved to be
well-tolerated and therapeutically effective. Teveten Plus HCT 600 mg/12.5 mg reduced systolic and diastolic blood pressure to a clinically relevant extent and was considered to
be statistically confirmed in the effects of both individual components and in the placebo
effect in spite of a high placebo response (p = 0.08 in the comparison of eprosartan alone
with placebo). The tolerability of eprosartan/hydrochlorothiazide 600 mg/12.5 mg was
comparable with that of eprosartan alone and that of placebo.
In another study, patients with a diastolic blood pressure between 98 and 114 mmHg who
did not respond sufficiently to 600 mg eprosartan received the combination Teveten Plus
HCT 600 mg/12.5 mg or maintained the monotherapy with 600 mg eprosartan for a further
8 weeks. The combination resulted in a statistically significant and clinically relevant
additional systolic and diastolic blood pressure reduction in patients who had not shown a
satisfactory reduction of blood pressure with the monotherapy. Tolerability under the
combination and the monotherapy was equally good.
Only limited data are available on patients aged over 80.
The effect of the combination of eprosartan and hydrochlorothiazide on morbidity and
mortality has not been studied. Epidemiological studies have shown that long-term
treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and
morbidity.
In two big randomised controlled studies (“ONTARGET” [ONgoing Telmisartan Alone
and in combination with Ramipril Global Endpoint Trial] und “VA NEPHRON-D” [The
Veterans Affairs Nephropathy in Diabetes]) the concomitant use of an ACE inhibitor with
an angiotensin II receptor antagonist was investigated.
The “ONTARGET” study was carried out in patients with a history of cardiovascular or
cerebrovascular disease or with type 2 diabetes mellitus with confirmed target organ
damage. The “VA NEPHRON-D” study was carried out in patients with type 2 diabetes
mellitus and diabetic nephropathy.
These studies showed no significant beneficial effects from renal and/or cardiovascular
endpoints and mortality, while a higher risk of hyperkalaemia, acute renal damage and/or
hypotension was observed compared with monotherapy. Because of the comparable
pharmacodynamic properties these results can also be transferred to other ACE inhibitors
and angiotensin II receptor antagonists.
For this reason ACE inhibitors and angiotensin II receptor antagonists should not be used
concomitantly in patients with diabetic nephropathy.
The “ALTITUDE” study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and
Renal Disease Endpoints) investigated whether the use of aliskiren in addition to a
standard therapy with an ACE inhibitor or angiotensin II receptor antagonists in patients
with type 2 diabetes mellitus as well as chronic renal disease and/or cardiovascular disease
had any additional benefit. The study was ended prematurely because of an increased risk
of unwanted events. Both cardiovascular deaths and strokes occurred in the aliskiren
group numerically more frequently than in the placebo group, as well as unwanted events
and particularly serious unwanted events (hyperkalaemia, hypotension, renal function
disorder).

EprosartanAfter oral administration, absolute bioavailability of eprosartan is about 13%. The peak
plasma concentration of eprosartan is reached 1 to 2 hours after administration when
fasting. The terminal elimination half-life of eprosartan is 5 to 9 hours. After long-term
administration of eprosartan, a slight accumulation occurs (14%). Taking eprosartan with
food delays absorption, but does not reduce bioavailability.

In a dose-range between 100 and 800 mg, the plasma concentration increases slightly less
than dose-proportional. This effect is probably explained by the physicochemical
properties of the substance.
Plasma protein binding of eprosartan is 98% and is not influenced by gender, age, liver
function disorders or mild to moderate renal impairment. Plasma protein binding is
reduced in a small number of patients with severe renal impairment.
The volume of distribution of eprosartan is approx. 13 l and total plasma clearance is
approx. 130 ml/min. After oral administration of [14C] eprosartan, about 90% of
radioactivity is recovered in the faeces. About 7% was excreted in urine, 80% of which as
eprosartan.
Both AUC and Cmax values of eprosartan are higher in elderly patients (on average around
twofold). No dosage adjustment is necessary.
AUC values of eprosartan (but not Cmax values) are increased in patients with hepatic
impairment on average by about 40%. No dosage adjustment is necessary.
Compared with test subjects with normal renal function, mean AUC and Cmax values were
approximately 30% higher in patients with moderate renal impairment (creatinine
clearance: 30 – 59 ml/min) and were approximately 50% higher in patients with severe
renal impairment (creatinine clearance: 5 – 29 ml/min). There is no difference between
men and women in the pharmacokinetics.
In vitro eprosartan did not inhibit human cytochrome P450 isoenzymes CYP1A, 2A6,
2C9/8, 2C19, 2D6, 2E and 3A.
Hydrochlorothiazide
After oral administration, absorption of hydrochlorothiazide was relatively quick. If
administered whilst fasting, the average elimination half-life is 5 – 15 hours.
Hydrochlorothiazide is not metabolised; it is immediately excreted via the kidneys. At
least 61% of the oral dose is excreted unchanged within 24 hours. Hydrochlorothiazide
crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Teveten Plus HCT 600 mg/12.5 mg
Concomitant administration of hydrochlorothiazide and eprosartan has no clinically
significant effect on the pharmacokinetics of either of the individual active substances.
The bioavailability of eprosartan and hydrochlorothiazide is not influenced by food, but
absorption is delayed. The highest plasma concentrations are reached after 4 hours for
eprosartan and after 3 hours for hydrochlorothiazide.

The potential toxicity of the combination eprosartan/hydrochlorothiazide after oral
administration was studied for up to 3 months in mouse and dog toxicity studies. There
were no findings that ruled out the use of therapeutic doses in humans.
The toxicological target organ was the kidney. The combination eprosartan/
hydrochlorothiazide caused functional kidney changes (increases in the serum urea and
plasma creatinine). Furthermore, higher doses caused tubular degeneration and
regeneration in the kidney in mice and dogs, probably through a change in the renal
haemodynamics (obstructed renal perfusion as a result of hypotension and the resultant
hypoxia of the kidney tubules with cell degeneration in the tubules). The combination also
caused hyperplasia of the juxtaglomerular cells, a decrease in the red blood cell
parameters and reductions in heart weight. These changes seemed to be triggered by the
pharmacological effects of higher eprosartan doses and also occur with ACE inhibitors.
The relevance of these changes for the use of therapeutic doses of the
eprosartan/hydrochlorothiazide combination is unknown in humans.

The findings from the in vitro and in vivo studies, both with the individual substances and
with the combination, showed that eprosartan/
hydrochlorothiazide has no relevant genotoxic potential.
No carcinogenicity studies were carried out with the combination
eprosartan/hydrochlorothiazide. In rats and mice given 600 or 2000 mg/kg of body weight
of eprosartan per day respectively for 2 years, no signs of carcinogenicity were found.
In pregnant rabbits at a dose of 10 mg/kg body weight/day, eprosartan only showed
maternal and foetal mortality in the late stage of pregnancy. Hydrochlorothiazide did not
increase the maternal and embryofoetal toxicity of eprosartan. At a daily dose of the active
substance combination (eprosartan/hydrochlorothiazide) of up to 3/1 mg/kg body
weight/day, no maternal or foetal toxic effects were revealed.

Tablet core
Lactose monohydrate
Microcrystalline cellulose
Pregelatinised starch (maize)
Crospovidone (Type B acc. to Ph. Eur.)
Magnesium stearate (Ph. Eur.) [vegetable]
Purified water
Tablet coating
Polyvinyl alcohol
Talc
Titanium dioxide (E171)
Macrogol 3350
Iron (II,III) oxide (E172)
Iron (III) oxide-hydroxide x H2O (E172)

Not applicable.

3 years

Store below 30°C.

Teveten Plus is provided in blisters containing 7, 14, 28, 56, and 98 tablets.
The blister packs are made of opaque PVC/PCTFE/Alu.
Not all pack sizes may be marketed.

No special requirements.