Treatment of essential hypertension as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of amlodipine, valsartan and hydrochlorothiazide (HCT), taken either as three single-component formulations or as a dual-component and a single-component formulation.

Posology

The recommended dose of Lotevan Plus is one tablet per day, to be taken preferably in the

morning.

Before switching to Lotevan Plus patients should be controlled on stable doses of the

monocomponents taken at the same time. The dose of Lotevan Plus should be based on the

doses of the individual components of the combination at the time of switching.

The maximum recommended dose of Lotevan Plus is 10 mg/320 mg/25 mg.

Special populations

Renal impairment

No adjustment of the initial dose is required for patients with mild to moderate renal

impairment (see sections 4.4 and 5.2). Due to the hydrochlorothiazide component, Lotevan

Plus is contraindicated for use in patients with anuria (see section 4.3) and in patients with

severe renal impairment (glomerular filtration rate (GFR) <30 ml/min/1.73 m2) (see

sections 4.3, 4.4 and 5.2).

The concomitant use of Lotevan Plus with aliskiren is contraindicated in patients with renal

impairment (GFR <60 ml/min/1.73 m2) (see section 4.3).

Diabetes mellitus

The concomitant use of Lotevan Plus with aliskiren is contraindicated in patients with

diabetes mellitus (see section 4.3).

Hepatic impairment

Due to the valsartan component, Lotevan Plus is contraindicated in patients with severe

hepatic impairment (see section 4.3). In patients with mild to moderate hepatic impairment

without cholestasis, the maximum recommended dose is 80 mg valsartan and therefore 

Lotevan Plus is not suitable in this group of patients (see sections 4.3, 4.4 and 5.2).

Amlodipine dosage recommendations have not been established in patients with mild to

moderate hepatic impairment.

Heart failure and coronary artery disease

There is limited experience with the use of Lotevan Plus, particulary at the maximum dose,

in patients with heart failure and coronary artery disease. Caution is advised in patients with

heart failure and coronary artery disease, particularly at the maximum dose of Lotevan Plus,

10 mg/320 mg/25 mg.

Elderly (age 65 years or over)

Caution, including more frequent monitoring of blood pressure, is recommended in elderly

patients, particularly at the maximum dose of Lotevan Plus, 10 mg/320 mg/25 mg, since

available data in this patient population are limited.

Paediatric population

There is no relevant use of Lotevan Plus in the paediatric population (patients below age 18

years) for the indication of essential hypertension.

Method of administration

Lotevan Plus can be taken with or without food. The tablets should be swallowed whole

with some water, at the same time of the day and preferably in the morning.

- Hypersensitivity to the active substances, to other sulphonamide derivatives, to dihydropyridine derivatives, or to any of the excipients. - Second and third trimesters of pregnancy (see sections 4.4 and 4.6). - Hepatic impairment, biliary cirrhosis or cholestasis. - Severe renal impairment (GFR <30 ml/min/1.73 m2), anuria and patients undergoing dialysis. - Concomitant use of angiotensin receptor antagonists (ARB) - including valsartan - or of angiotensin converting enzyme (ACE) inhibitors with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.4 and 4.5). - Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia. - Severe hypotension. - Shock (including cardiogenic shock). - Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy and high grade aortic stenosis). - Haemodynamically unstable heart failure after acute myocardial infarction.

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

Sodium- and/or volume-depleted patients

Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients

treated with the maximum dose of Lotevan Plus (10 mg/320 mg/25 mg) compared to 1.8% of

valsartan/hydrochlorothiazide (320 mg/25 mg) patients, 0.4% of amlodipine/valsartan (10 

mg/320 mg) patients, and 0.2% of hydrochlorothiazide/amlodipine (25 mg/10 mg) patients in

a controlled trial in patients with moderate to severe uncomplicated hypertension.

In sodium-depleted and/or volume-depleted patients, such as those receiving high doses of

diuretics, symptomatic hypotension may occur after initiation of treatment with Lotevan Plus.

Lotevan Plus should be used only after correction of any pre-existing sodium and/or volume

depletion.

If excessive hypotension occurs with Lotevan Plus, the patient should be placed in the supine

position and, if necessary, given an intravenous infusion of normal saline. Treatment can be

continued once blood pressure has been stabilised.

Serum electrolyte changes

Amlodipine/valsartan/hydrochlorothiazide

In the controlled trial of Lotevan Plus, the counteracting effects of valsartan 320 mg and

hydrochlorothiazide 25 mg on serum potassium approximately balanced each other in many

patients. In other patients, one or the other effect may be dominant. Periodic determinations

of serum electrolytes to detect possible electrolyte imbalance should be performed at

appropriate intervals.

Periodic determination of serum electrolytes and potassium in particular should be performed

at appropriate intervals to detect possible electrolyte imbalance, especially in patients with

other risk factors such as impaired renal function, treatment with other medicinal products or

history of prior electrolyte imbalances.

Valsartan

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes

containing potassium, or other medicinal products that may increase potassium levels

(heparin, etc.) is not recommended. Monitoring of potassium should be undertaken as

appropriate.

Hydrochlorothiazide

Treatment with Lotevan Plus should only start after correction of hypokalaemia and any

coexisting hypomagnesaemia. Thiazide diuretics can precipitate new onset hypokalaemia or

exacerbate pre-existing hypokalaemia. Thiazide diuretics should be administered with caution

in patients with conditions involving enhanced potassium loss, for example salt-losing

nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalaemia

develops during hydrochlorothiazide therapy, Lotevan Plus should be discontinued until

stable correction of the potassium balance.

Thiazide diuretics can precipitate new onset hyponatraemia and hypochloroaemic alkalosis or

exacerbate pre-existing hyponatraemia. Hyponatraemia, accompanied by neurological

symptoms (nausea, progressive disorientation, apathy) has been observed. Treatment with

hydrochlorothiazide should only be started after correction of pre-existing hyponatraemia. In

case severe or rapid hyponatraemia develops during Lotevan Plus therapy, the treatment

should be discontinued until normalisation of natraemia.

All patients receiving thiazide diuretics should be periodically monitored for imbalances in

electrolytes, particularly potassium, sodium and magnesium. 

Renal impairment

Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. When

Lotevan Plus is used in patients with renal impairment periodic monitoring of serum

electrolytes (including potassium), creatinine and uric acid serum levels is recommended.

Lotevan Plus is contraindicated in patients with severe renal impairment, anuria or

undergoing dialysis (see section 4.3).

No dosage adjustment of Lotevan Plus is required for patients with mild to moderate renal

impairment (GFR ≥30 ml/min/1.73 m2).

The concomitant use of ARBs - including valsartan - or of ACE inhibitors with aliskiren is

contraindicated in patients with renal impairment (GFR <60 ml/min/1.73 m2) (see sections

4.3 and 4.5).

Renal artery stenosis

Lotevan Plus should be used with caution to treat hypertension in patients with unilateral or

bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum

creatinine may increase in such patients.

Kidney transplantation

To date there is no experience of the safe use of Lotevan Plus in patients who have had a

recent kidney transplantation.

Hepatic impairment

Valsartan is mostly eliminated unchanged via the bile. The half life of amlodipine is

prolonged and AUC values are higher in patients with impaired liver function; dosage

recommendations have not been established. In patients with mild to moderate hepatic

impairment without cholestasis, the maximum recommended dose is 80 mg valsartan, and

therefore, Lotevan Plus is not suitable in this group of patients (see sections 4.2, 4.3 and 5.2).

Angioedema

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or

swelling of the face, lips, pharynx, and/or tongue, has been reported in patients treated with

valsartan. Some of these patients previously experienced angioedema with other medicinal

products including ACE inhibitors. Lotevan Plus should be discontinued immediately in

patients who develop angioedema and should not be re-administered.

Heart failure and coronary artery disease/post-myocardial infarction

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in

renal function may be anticipated in susceptible individuals. In patients with severe heart

failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone

system, treatment with ACE inhibitors and angiotensin receptor antagonists has been

associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure

and/or death. Similar outcomes have been reported with valsartan. Evaluation of patients with

heart failure or post-myocardial infarction should always include assessment of renal

function.

In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA

(New York Heart Association Classification) III and IV heart failure of non-ischaemic 

aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no

significant difference in the incidence of worsening heart failure as compared to placebo.

Calcium channel blockers, including amlodipine, should be used with caution in patients with

congestive heart failure, as they may increase the risk of future cardiovascular events and

mortality.

Caution is advised in patients with heart failure and coronary artery disease, particularly at

the maximum dose of Lotevan Plus, 10 mg/320 mg/25 mg, since available data in these

patient populations is limited.

Aortic and mitral valve stenosis

As with all other vasodilators, special caution is indicated in patients with mitral stenosis or

significant aortic stenosis that is not high grade.

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.

Unless continued AIIRA therapy is considered essential, patients planning pregnancy should

be changed to alternative antihypertensive treatments which have an established safety profile

for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be

stopped immediately, and, if appropriate, alternative therapy should be started (see sections

4.3 and 4.6).

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with the angiotensin II

antagonist valsartan as their renin-angiotensin system is not activated. Therefore, Lotevan

Plus is not recommended in this population.

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or

activate systemic lupus erythematosus.

Other metabolic disturbances

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise

serum levels of cholesterol, triglycerides and uric acid. In diabetic patients dosage

adjustments of insulin or oral hypoglycaemic agents may be required.

Due to the hydrochlorothiazide component, Lotevan Plus is contraindicated in symptomatic

hyperuricaemia. Hydrochlorothiazide may raise the serum uric acid level due to reduced

clearance of uric acid and may cause or exacerbate hyperuricaemia as well as precipitate gout

in susceptible patients.

Thiazides reduce urinary calcium excretion and may cause intermittant and slight elevation of

serum calcium in the absence of known disorders of calcium metabolism. Lotevan Plus is

contraindicated in patients with hypercalcaemia and should only be used after correction of

any pre-existing hypercalcaemia. Lotevan Plus should be discontinued if hypercalcaemia

develops during treatment. Serum levels of calcium should be periodically monitored during

treatment with thiazides. Marked hypercalcaemia may be evidence of hidden

hyperparathyroidism. Thiazides should be discontinued before carrying out tests for

parathyroid function.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section

4.8). If photosensitivity reaction occurs during treatment with Lotevan Plus, it is

recommended to stop the treatment. If a readministration of the diuretic is deemed necessary,

it is recommended to protect exposed areas to the sun or to artificial UVA.

Acute angle-closure glaucoma

Hydrochlorothiazide, a sulphonamide, has been associated with an idiosyncratic reaction

resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include

acute onset of decreased visual acuity or ocular pain and typically occur within hours to a

week of treatment initiation. Untreated acute-angle closure glaucoma can lead to permanent

vision loss.

The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt

medical or surgical treatment may need to be considered if the intraocular pressure remains

uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history

of sulphonamide or penicillin allergy.

General

Caution should be exercised in patients who have shown prior hypersensitivity to other

angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are

more likely in patients with allergy and asthma.

Elderly (age 65 years or over)

Caution, including more frequent monitoring of blood pressure, is recommended in elderly

patients, particularly at the maximum dose of Lotevan Plus, 10 mg/320 mg/25 mg, since

available data in this patient population are limited.

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

The concomitant use of ARBs, including valsartan, with other agents acting on the RAAS is

associated with an increased incidence of hypotension, hyperkalaemia, and changes in renal

function compared to monotherapy. It is recommended to monitor blood pressure, renal

function and electrolytes in patients on Lotevan Plus and other agents that affect the RAAS.

Caution is required when co-administering ARBs - including valsartan - with other agents

blocking the RAAS such as ACE inhibitors or aliskiren (see section 4.5).

The concomitant use of ARBs - including valsartan - or of ACE inhibitors with aliskiren in

patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) is

contraindicated (see sections 4.3 and 4.5).

No formal interaction studies with other medicinal products were performed with Lotevan Plus. Thus, only information on interactions with other medicinal products that are known for the individual active substances is provided in this section.

However, it is important to take into account that Lotevan Plus may increase the hypotensive effect of other antihypertensive agents.

Concomitant use not recommended

Lotevan Plus individual component	Known interactions with the following agents	Effect of the interaction with other medicinal products
Valsartan and HCT	Lithium	Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors and thiazides such as hydrochlorothiazide. Despite the lack of experience with concomitant use of valsartan and lithium, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended (see section 4.4).
Valsartan	Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels	If a medicinal product that affects potassium levels is considered necessary in combination with valsartan, frequent monitoring of potassium plasma levels is advised.
Amlodipine	Grapefruit or grapefruit juice	Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients, resulting in increased blood pressure lowering effects.

Caution required with concomitant use

Lotevan Plus individual component	Known interactions with the following agents	Effect of the interaction with other medicinal products
Amlodipine	CYP3A4 inhibitors (i.e. ketoconazole, itraconazole, ritonavir)	Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
	CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, Hypericum perforatum [St. John’s wort])	There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.
	Simvastatin	Co-administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose of simvastatin to 20 mg daily in patients on amlodipine.
	Dantrolene (infusion)	In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
Valsartan and HCT	Non-steroidal anti-inflammatory medicines (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), acetylsalicylic acid (>3 g/day), and non-selective NSAIDs	NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of Lotevan Plus and NSAIDs may lead to worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.
Valsartan	Inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir)	The results of an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and of the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
HCT	Alcohol, barbiturates or narcotics	Concomitant administration of thiazide diuretics with substances that also have a blood pressure lowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation) may potentiate orthostatic hypotension.
	Amantadine	Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions caused by amantadine.
	Anticholinergic agents and other medicinal products affecting gastric motility	The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, it is anticipated that prokinetic substances such as cisapride may decrease the bioavailability of thiazide-type diuretics.
	Antidiabetic agents (e.g. insulin and oral antidiabetic agents)	Thiazides may alter glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be necessary.
	-   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	Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycaemic effect of diazoxide.
	Ciclosporin	Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.
	Cytotoxic agents	Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic agents (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
	Digitalis glycosides	Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects, favouring the onset of digitalis-induced cardiac arrhythmias.
	Iodine contrasting agents	In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine products. Patients should be re-hydrated before the administration.
	Ion exchange resins	Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins would potentially minimise the interaction.
	Medicinal products affecting serum potassium level	The hypokalaemic effect of hydrochlorothiazide may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G and salicylic acid derivatives or antiarrhythmics. If these medicinal products are to be prescribed with the amlodipine /valsartan /hydrochlorothiazide combination, monitoring of potassium plasma levels is advised.
	Medicinal products affecting serum sodium level	The hyponatraemic effect of diuretics may be intensified by concomitant administration of medicinal products such as antidepressants, antipsychotics, antiepileptics, etc. Caution is indicated in long-term administration of these medicinal products.
	Medicinal products that could induce torsades de pointes	Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when associated with medicinal products that could induce torsades de pointes, in particular Class Ia and Class III antiarrhythmics and some antipsychotics.
	Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol)	Dose adjustment of uricosuric medicinal products may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase of dose of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.
	Methyldopa	There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
	Non-depolarising skeletal muscle relaxants (e.g. tubocurarine)	Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.
	Other anti-hypertensive drugs	Thiazides potentiate the antihypertensive action of other antihypertensive drugs (e.g. guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, ARBs and Direct Renin Inhibitors [DRIs]).
	Pressor amines (e.g. noradrenaline, adrenaline)	Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.
	Vitamin D and calcium salts	Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium. Concomitant use of thiazide type diuretics may lead to hypercalcaemia in patients pre-disposed for hypercalcaemia (e.g. hyperparathyroidism, malignancy or vitamin-D-mediated conditions) by increasing tubular calcium reabsorption.

No interaction

Lotevan Plus individual component	Known interactions with the following agents	Effect of the interaction with other medicinal products
Valsartan	Others (cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipine, glibenclamide)	In monotherapy with valsartan, no interactions of clinical significance have been found with the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Some of these substances could interact with the hydrochlorothiazide component of Lotevan Plus (see interactions related to HCT).
Amlodipine	Others	In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or ciclosporin.

Dual blockade of the RAAS with ARBs, ACE inhibitors or aliskiren

The concomitant use of ARBs - including valsartan - or of ACE inhibitors with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m²) (see sections 4.3 and 4.4).

Pregnancy

Amlodipine

The safety of amlodipine in human pregnancy has not been established. In animal studies,

reproductive toxicity was observed at high doses (see section 5.3). Use in pregnancy is only

recommended when there is no safer alternative and when the disease itself carries greater

risk for the mother and foetus.

Valsartan

Pregnancy Category D

Valsartan, like other drugs that act on the renin angiotensin system, can cause fetal and

neonatal morbidity and death when used during the second or third trimester of pregnancy. If

Lotevan Plus is used during pregnancy, or if the patient becomes pregnant while taking this

drug, the patient should be apprised of the potential hazard to the fetus.

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy (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).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE

inhibitors during the first trimester of pregnancy has not been conclusive; however a small

increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the

risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class

of drugs. Unless continued AIIRA therapy is considered essential, patients planning

pregnancy should be changed to alternative antihypertensive treatments which have an

established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with

AIIRAs should be stopped immediately, and if appropriate, alternative therapy should be

started.

Exposure to AIIRAs therapy during the second and third trimesters is known to induce

human foetotoxicity (decreased renal function, oligohydramnios, skull ossification

retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section

5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy,

ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see

sections 4.3 and 4.4).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first

trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of

hydrochlorothiazide, its use during the second and third trimester may compromise foeto-placental

perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and

thrombocytopenia.

Amlodipine/valsartan/hydrochlorothiazide

There is no experience on the use of Lotevan Plus in pregnant women. Based on the existing data with

the components, the use of Lotevan Plus is not recommended during first trimester and contraindicated

during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Breast-feeding

No information is available regarding the use of valsartan and/or amlodipine during breastfeeding.

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high

doses causing intense diuresis can inhibit milk production. The use of Lotevan Plus during

breast-feeding is not recommended. If Lotevan Plus is used during breast-feeding, doses

should be kept as low as possible. Alternative treatments with better established safety

profiles during breast-feeding are preferable, especially while nursing a newborn or preterm

infant.

Fertility

There are no clinical studies on fertility with Lotevan Plus.

Valsartan

Valsartan had no adverse effects on the reproductive performance of male or female rats at

oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human

dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).

Amlodipine

Reversible biochemical changes in the head of spermatozoa have been reported in some

patients treated by calcium channel blockers. Clinical data are insufficient regarding the

potential effect of amlodipine on fertility. In one rat study, adverse effects were found on

male fertility (see section 5.3).

Patients taking Lotevan Plus and driving vehicles or using machines should take into account

that dizziness or weariness may occasionally occur.

Amlodipine can have mild or moderate influence on the ability to drive and use machines. If

patients taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to

react may be impaired.

The safety profile of Lotevan Plus presented below is based on clinical studies performed

with Lotevan Plus and the known safety profile of the individual components amlodipine,

valsartan and hydrochlorothiazide.

Information on Lotevan Plus

The safety of Lotevan Plus has been evaluated at its maximum dose of 10 mg/320 mg/25 mg

in one controlled short-term (8 weeks) clinical study with 2,271 patients, 582 of whom

received valsartan in combination with amlodipine and hydrochlorothiazide. Adverse

reactions were generally mild and transient in nature and only infrequently required

discontinuation of therapy. In this active controlled clinical trial, the most common reasons

for discontinuation of therapy with Lotevan Plus were dizziness and hypotension (0.7%).

In the 8-week controlled clinical study, no significant new or unexpected adverse reactions

were observed with triple therapy treatment compared to the known effects of the

monotherapy or dual therapy components.

In the 8-week controlled clinical study, changes in laboratory parameters observed with the

combination of Lotevan Plus were minor and consistent with the pharmacological mechanism

of action of the monotherapy agents. The presence of valsartan in the triple combination

attenuated the hypokalaemic effect of hydrochlorothiazide.

The following adverse reactions, listed by MedDRA System Organ Class and frequency,

concern Lotevan Plus (amlodipine/valsartan/HCT) and amlodipine, valsartan and HCT

individually.

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, not known (cannot be estimated from the

available data).

MedDRA System Organ Class	Adverse reactions	Frequency
		Lotevan Plus	Amlodipine	Valsartan	HCT
Blood and lymphatic system disorders	Agranulocytosis, bone marrow depression	--	--	--	Very rare
	Decrease in haemoglobin and in haematocrit	--	--	Not known	--
	Haemolytic anaemia	--	--	--	Very rare
	Leukopenia	--	Very rare	--	Very rare
	Neutropenia	--	--	Not known	--
	Thrombocytopenia, sometimes with purpura	--	Very rare	Not known	Rare
	Aplastic anaemia	--	--	--	Not known
Immune system disorders	Hypersensitivity	--	Very rare	Not known	Very rare
Metabolism and nutrition disorders	Anorexia	Uncommon	--	--	--
	Hypercalcaemia	Uncommon	--	--	Rare
	Hyperglycaemia	--	Very rare	--	Rare
	Hyperlipidaemia	Uncommon	--	--	--
	Hyperuricaemia	Uncommon	--	--	Common
	Hypochloraemic alkalosis	--	--	--	Very rare
	Hypokalaemia	Common	--	--	Very common
	Hypomagnesaemia	--	--	--	Common
	Hyponatraemia	Uncommon	--	--	Common
	Worsening of diabetic metabolic state	--	--	--	Rare
Psychiatric disorders	Depression	--	Uncommon	--	Rare
	Insomnia/sleep disturbances	Uncommon	Uncommon	--	Rare
	Mood swings	--	Uncommon	--
	Confusion	--	Rare	--	--
Nervous system disorders	Coordination abnormal	Uncommon	--	--	--
	Dizziness	Common	Common	--	Rare
	Dizziness postural, dizziness exertional	Uncommon	--	--	--
	Dysgeusia	Uncommon	Uncommon	--	--
	Extrapyramidal syndrome	--	Not known	--	--
	Headache	Common	Common	--	Rare
	Hypertonia	--	Very rare	--	--
	Lethargy	Uncommon	--	--	--
	Paraesthesia	Uncommon	Uncommon	--	Rare
	Peripheral neuropathy, neuropathy	Uncommon	Very rare	--	--
	Somnolence	Uncommon	Common	--	--
	Syncope	Uncommon	Uncommon	--	--
	Tremor	--	Uncommon	--	--
	Hypoesthesia	--	Uncommon	--	--
Eye disorders	Acute angle-closure glaucoma	--	--	--	Not known
	Visual disturbance	--	Uncommon	--	--
	Visual impairment	Uncommon	Uncommon	--	Rare
	Choroidal effusion, acute myopia				Not known
Ear and labyrinth disorders	Tinnitus	--	Uncommon	--	--
	Vertigo	Uncommon	--	Uncommon	--
Cardiac disorders	Palpitations	--	Common	--	--
	Tachycardia	Uncommon	--	--	--
	Arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation)	--	Very rare	--	Rare
	Myocardial infarction	--	Very rare	--	--
Vascular disorders	Flushing	--	Common	--	--
	Hypotension	Common	Uncommon	--	--
	Orthostatic hypotension	Uncommon	--	--	Common
	Phlebitis, thrombophlebitis	Uncommon	--	--	--
	Vasculitis	--	Very rare	Not known	--
Respiratory, thoracic and mediastinal disorders	Cough	Uncommon	Very rare	Uncommon	--
	Dyspnoea	Uncommon	Uncommon	--	--
	Respiratory distress, pulmonary oedema, pneumonitis	--	--	--	Very rare
	Rhinitis	--	Uncommon	--	--
	Throat irritation	Uncommon	--	--	--
Gastrointestinal disorders	Abdominal discomfort, abdominal pain upper	Uncommon	Common	Uncommon	Rare
	Breath odour	Uncommon	--	--	--
	Change of bowel habit	--	Uncommon	--	--
	Constipation	--	--	--	Rare
	Decreased appetite	--	--	--	Common
	Diarrhoea	Uncommon	Uncommon	--	Rare
	Dry mouth	Uncommon	Uncommon	--	--
	Dyspepsia	Common	Uncommon	--	--
	Gastritis	--	Very rare	--	--
	Gingival hyperplasia	--	Very rare	--	--
	Nausea	Uncommon	Common	--	Common
	Pancreatitis	--	Very rare	--	Very rare
	Vomiting	Uncommon	Uncommon	--	Common
Hepatobiliary disorders	Hepatic enzyme elevation, including increase of serum bilirubin	--	Very rare**	Not known	--
	Hepatitis	--	Very rare	--	--
	Intrahepatic cholestasis, jaundice	--	Very rare	--	Rare
Skin and subcutaneous tissue disorders	Alopecia	--	Uncommon	--
	Angioedema	--	Very rare	Not known	--
	Cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus	--	--	--	Very rare
	Erythema multiforme	--	Very rare	--	Not known
	Exanthema	--	Uncommon	--	--
	Hyperhidrosis	Uncommon	Uncommon	--	--
	Photosensitivity reaction*	--	Very rare	--	Rare
	Pruritus	Uncommon	Uncommon	Not known	--
	Purpura	--	Uncommon	--	Rare
	Rash	--	Uncommon	Not known	Common
	Skin discoloration	--	Uncommon	--	--
	Urticaria and other forms of rash	--	Very rare	--	Common
	Vasculitis necrotising and toxic epidermal necrolysis	--	--	--	Very rare
	Exfoliative dermatitis	--	Very rare	--	--
	Stevens-Johnson syndrome	--	Very rare	--	--
	Quincke oedema	--	Very rare	--	--
Musculoskeletal and connective tissue disorders	Arthralgia	--	Uncommon	--	--
	Back pain	Uncommon	Uncommon	--	--
	Joint swelling	Uncommon	--	--	--
	Muscle spasm	Uncommon	Uncommon	--	Not known
	Muscular weakness	Uncommon	--	--	--
	Myalgia	Uncommon	Uncommon	Not known	--
	Pain in extremity	Uncommon	--	--	--
	Ankle swelling	--	Common	--	--
Renal and urinary disorders	Elevation of serum creatinine	Uncommon	--	Not known	--
	Micturition disorder		Uncommon
	Nocturia	--	Uncommon	--	--
	Pollakiuria	Common	Uncommon
	Renal dysfunction	--	--	--	Not known
	Renal failure acute	Uncommon	--	--	Not known
	Renal failure and impairment	--	--	Not known	Rare
Reproductive system and breast disorders	Impotence	Uncommon	Uncommon	--	Common
	Gynaecomastia		Uncommon	--	--
General disorders and administration site conditions	Abasia, gait disturbance	Uncommon	--	--	--
	Asthenia	Uncommon	Uncommon	--	Not known
	Discomfort, malaise	Uncommon	Uncommon	--	--
	Fatigue	Common	Common	Uncommon	--
	Non cardiac chest pain	Uncommon	Uncommon	--	--
	Oedema	Common	Common	--	--
	Pain	--	Uncommon	--	--
	Pyrexia	--	--	--	Not known
Investigations	Lipids increased		--		Very common
	Blood urea nitrogen increased	Uncommon	--	--	--
	Blood uric acid increased	Uncommon	--	--
	Glycosuria				Rare
	Serum potassium decreased	Uncommon	--	--	--
	Serum potassium increased	--	--	Not known	--
	Weight increase	Uncommon	Uncommon	--	--
	Weight decrease	--	Uncommon	--	--

* See section 4.4 Photosensitivity

** Mostly consistent with cholestasis

To reports any side effect(s):

The National Pharmacovigilance and Drug Safety Centre (NPC)

o Fax: +966-11-205-7662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

o Toll free phone: 8002490000

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

o Website: www.sfda.gov.sa/npc

Symptoms

There is no experience of overdose with Lotevan Plus. The major symptom of overdose with

valsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine may

result in excessive peripheral vasodilation and, possibly, reflex tachycardia. Marked and

potentially prolonged systemic hypotension, including shock with fatal outcome, have been

reported with amlodipine.

Treatment

Amlodipine/Valsartan/Hydrochlorothiazide

Clinically significant hypotension due to Lotevan Plus overdose calls for active

cardiovascular support, including frequent monitoring of cardiac and respiratory function,

elevation of extremities, and attention to circulating fluid volume and urine output. A

vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that

there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in

reversing the effects of calcium channel blockade.

Amlodipine

If ingestion is recent, induction of vomiting or gastric lavage may be considered.

Administration of activated charcoal to healthy volunteers immediately or up to two hours

after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.

Amlodipine is unlikely to be removed by haemodialysis 

Valsartan

Valsartan is unlikely to be removed by haemodialysis.

Hydrochlorothiazide

Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia,

hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most common

signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in

muscle spasms and or accentuate arrhythmia associated with the concomitant use of digitalis

glycosides or certain anti-arrhythmic medicinal products.

The degree to which hydrochlorothiazide is removed by haemodialysis has not been

established.

ATC Code:

Valsartan and Diuretics: C09DA03.

Valsartan and Amlodipine: C09DB01.

Pharmacotherapeutic group:

Angiotensin II antagonists, plain (valsartan), combinations with dihydropyridine derivatives

(amlodipine) and thiazide diuretics (hydrochlorothiazide).

Lotevan Plus combines three antihypertensive compounds with complementary mechanisms

to control blood pressure in patients with essential hypertension: amlodipine belongs to the

calcium antagonist class and valsartan to the angiotensin II antagonist class of medicines and

hydrochlorothiazide belongs to the thiazide diuretics class of medicines. The combination of

these substances has an additive antihypertensive effect.

Amlodipine/Valsartan/Hydrochlorothiazide

Lotevan Plus was studied in a double-blind, active controlled study in hypertensive patients.

A total of 2,271 patients with moderate to severe hypertension (mean baseline

systolic/diastolic blood pressure was 170/107 mmHg) received treatments of

amlodipine/valsartan/hydrochlorothiazide 10 mg/320 mg/25 mg,

valsartan/hydrochlorothiazide 320 mg/25 mg, amlodipine/valsartan 10 mg/320 mg, or

hydrochlorothiazide/amlodipine 25 mg/10 mg. At study initiation patients were assigned

lower doses of their treatment combination and were titrated to their full treatment dose by

week 2.

At week 8, the mean reductions in systolic/diastolic blood pressure were 39.7/24.7 mmHg

with Lotevan Plus, 32.0/19.7 mmHg with valsartan/hydrochlorothiazide, 33.5/21.5 mmHg

with amlodipine/valsartan, and 31.5/19.5 mmHg with amlodipine/hydrochlorothiazide. The

triple combination therapy was statistically superior to each of the three dual combination

treatments in reduction of diastolic and systolic blood pressures. The reductions in

systolic/diastolic blood pressure with Lotevan Plus were 7.6/5.0 mmHg greater than with

valsartan/hydrochlorothiazide, 6.2/3.3 mmHg greater than with amlodipine/valsartan, and

8.2/5.3 mmHg greater than with amlodipine/hydrochlorothiazide. The full blood pressure

lowering effect was achieved 2 weeks after being on their maximal dose of Lotevan Plus.  

Statistically greater proportions of patients achieved blood pressure control (<140/90 mmHg)

with Lotevan Plus (71%) compared to each of the three dual combination therapies (45-54%)

(p<0.0001).

In a subgroup of 283 patients focusing on ambulatory blood pressure monitoring, clinically

and statistically superior reductions in 24-hour systolic and diastolic blood pressures were

observed with the triple combination compared to valsartan/hydrochlorothiazide,

valsartan/amlodipine, and hydrochlorothiazide/amlodipine.

Amlodipine

The amlodipine component of Lotevan Plus inhibits the transmembrane entry of calcium ions

into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of

amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing reductions in

peripheral vascular resistance and in blood pressure. Experimental data suggest that

amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. The

contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the

movement of extracellular calcium ions into these cells through specific ion channels.

Following administration of therapeutic doses to patients with hypertension, amlodipine

produces vasodilation, resulting in a reduction of supine and standing blood pressures. These

decreases in blood pressure are not accompanied by a significant change in heart rate or

plasma catecholamine levels with chronic dosing.

Plasma concentrations correlate with effect in both young and elderly patients.

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted

in a decrease in renal vascular resistance and increases in glomerular filtration rate and

effective renal plasma flow, without change in filtration fraction or proteinuria.

As with other calcium channel blockers, haemodynamic measurements of cardiac function at

rest and during exercise (or pacing) in patients with normal ventricular function treated with

amlodipine have generally demonstrated a small increase in cardiac index without significant

influence on dP/dt or on left ventricular end diastolic pressure or volume. In haemodynamic

studies, amlodipine has not been associated with a negative inotropic effect when

administered in the therapeutic dose range to intact animals and humans, even when coadministered

with beta blockers to humans.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact

animals or humans. In clinical studies in which amlodipine was administered in combination

with beta blockers to patients with either hypertension or angina, no adverse effects on

electrocardiographic parameters were observed.

Amlodipine has been studied in patients with chronic stable angina, vasospastic angina and

angiographically documented coronary artery disease.

Use in patients with hypertension

A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid-

Lowering treatment to prevent Heart Attack Trial (ALLHAT) was performed to compare

newer therapies: amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40

mg/day (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone

12.5-25 mg/day in mild to moderate hypertension.

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a

mean of 4.9 years. The patients had at least one additional coronary heart disease risk factor,

including: previous myocardial infarction or stroke (>6 months prior to enrollment) or

documentation of other atherosclerotic cardiovascular disease (overall 51.5%), type 2

diabetes (36.1%), high density lipoprotein - cholesterol <35 mg/dl or <0.906 mmol/l (11.6%),

left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%),

current cigarette smoking (21.9%).

The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardial

infarction. There was no significant difference in the primary endpoint between amlodipinebased

therapy and chlorthalidone-based therapy: risk ratio (RR) 0.98 95% CI (0.90-1.07)

p=0.65. Among secondary endpoints, the incidence of heart failure (component of a

composite combined cardiovascular endpoint) was significantly higher in the amlodipine

group as compared to the chlorthalidone group (10.2% versus 7.7%, RR 1.38, 95% CI [1.25-

1.52] p<0.001). However, there was no significant difference in all-cause mortality between

amlodipine-based therapy and chlorthalidone-based therapy RR 0.96 95% CI [0.89-1.02]

p=0.20.

Valsartan

Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts

selectively on the receptor subtype AT1, which is responsible for the known actions of

angiotensin II.

Administration of valsartan to patients with hypertension results in a drop in blood pressure

without affecting pulse rate.

In most patients, after administration of a single oral dose, onset of antihypertensive activity

occurs within 2 hours, and the peak drop in blood pressure is achieved within 4-6 hours. The

antihypertensive effect persists over 24 hours after administration. During repeated

administration, the maximum reduction in blood pressure with any dose is generally attained

within 2-4 weeks.

Hydrochlorothiazide

The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has

been shown that there is a high-affinity receptor in the renal cortex as the primary binding site

for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted

tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter perhaps

by competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms: directly

increasing sodium and chloride excretion to an approximately equal extent, and indirectly, by

this diuretic action, reducing plasma volume, with consequent increases in plasma renin

activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium.

The European Medicines Agency has waived the obligation to submit the results of studies

with Lotevan Plus in all subsets of the paediatric population in essential hypertension. See

section 4.2 for information on paediatric use.

Linearity

Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics.

Amlodipine/valsartan/hydrochlorothiazide

Following oral administration of Lotevan Plus in normal healthy adults, peak plasma

concentrations of amlodipine, valsartan and hydrochlorothiazide are reached in 6-8 hours, 3

hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and

hydrochlorothiazide from Lotevan Plus are the same as when administered as individual

dosage forms.

Amlodipine

Absorption: After oral administration of therapeutic doses of amlodipine alone, peak plasma

concentrations of amlodipine are reached in 6-12 hours. Absolute bioavailability has been

calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by food

ingestion.

Distribution: Volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine

have shown that approximately 97.5% of circulating drug is bound to plasma proteins.

Biotransformation: Amlodipine is extensively (approximately 90%) metabolised in the liver to

inactive metabolites.

Elimination: Amlodipine elimination from plasma is biphasic, with a terminal elimination

half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after

continuous administration for 7-8 days. Ten per cent of original amlodipine and 60% of

amlodipine metabolites are excreted in urine.

Valsartan

Absorption: Following oral administration of valsartan alone, peak plasma concentrations of

valsartan are reached in 2-4 hours. Mean absolute bioavailability is 23%. Food decreases

exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration

(Cmax) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are

similar for the fed and fasted groups. This reduction in AUC is not, however, accompanied by

a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given

either with or without food.

Distribution: The steady-state volume of distribution of valsartan after intravenous

administration is about 17 litres, indicating that valsartan does not distribute into tissues

extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.

Biotransformation: Valsartan is not transformed to a high extent as only about 20% of dose is

recovered as metabolites. A hydroxy metabolite has been identified in plasma at low

concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically

inactive.

Elimination: Valsartan shows multiexponential decay kinetics (t½α <1 h and tóß about 9 h).

Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose),

mainly as unchanged drug. Following intravenous administration, plasma clearance of

valsartan is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of total clearance). The

half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption: The absorption of hydrochlorothiazide, after an oral dose, is rapid (Tmax about 2

hours). The increase in mean AUC is linear and dose proportional in the therapeutic range.

The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance.

Absolute bioavailability of hydrochlorothiazide is 70% after oral administration.

Distribution: The apparent volume of distribution is 4-8 l/kg. Circulating hydrochlorothiazide

is bound to serum proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also

accumulates in erythrocytes at approximately 3 times the level in plasma.

Biotransformation: Hydrochlorothiazide is eliminated predominantly as unchanged compound.

Elimination: Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15

hours in the terminal elimination phase. There is no change in the kinetics of

hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily.

More than 95% of the absorbed dose is being excreted as unchanged compound in the urine.

The renal clearance is composed of passive filtration and active secretion into the renal tubule.

Special populations

Paediatric patients (age below 18 years)

No pharmacokinetic data are available in the paediatric population.

Elderly (age 65 years or over)

Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In

elderly patients, amlodipine clearance tends to decline, causing increases in the area under the

curve (AUC) and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in

the elderly than in the young, therefore caution is required when increasing the dosage.

Systemic exposure to valsartan is slightly elevated in the elderly as compared to the young, but

this has not been shown to have any clinical significance.

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both

healthy and hypertensive elderly subjects compared to young healthy volunteers.

Since the three components are equally well tolerated in younger and elderly patients, normal

dose regimens are recommended (see section 4.2).

Renal impairment

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As

expected for a compound where renal clearance accounts for only 30% of total plasma

clearance, no correlation was seen between renal function and systemic exposure to valsartan.

Patients with mild to moderate renal impairment may therefore receive the usual initial dose

(see sections 4.2 and 4.4).

In the presence of renal impairment, mean peak plasma levels and AUC values of

hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with

mild to moderate renal impairment, a 3-fold increase in hydrochlorothiazide AUC has been

observed. In patients with severe renal impairment an 8-fold increase in AUC has been 

observed. Lotevan Plus is contraindicated in patients with severe renal impairment, anuria or

undergoing dialysis (see section 4.3).

Hepatic impairment

Very limited clinical data are available regarding amlodipine administration in patients with

hepatic impairment. Patients with hepatic impairment have decreased clearance of amlodipine

with resulting increase of approximately 40–60% in AUC. On average, in patients with mild to

moderate chronic liver disease, exposure (measured by AUC values) to valsartan is twice that

found in healthy volunteers (matched by age, sex and weight). Due to the valsartan

component, Lotevan Plus is contraindicated in patients with hepatic impairment (see sections

4.2 and 4.3).

Amlodipine/Valsartan/Hydrochlorothiazide

In a variety of preclinical safety studies conducted in several animal species with amlodipine,

valsartan, hydrochlorothiazide, valsartan/hydrochlorothiazide, amlodipine/valsartan and

amlodipine/valsartan/hydrochlorothiazide (Lotevan Plus), there was no evidence of systemic

or target organ toxicity that would adversely affect the development of Lotevan Plus for

clinical use in humans.

Preclinical safety studies of up to 13 weeks in duration were conducted with

amlodipine/valsartan/hydrochlorothiazide in rats. The combination resulted in expected

reduction of red blood cell mass (erythrocytes, haemoglobin, haematocrit, and reticulocytes),

increase in serum urea, increase in serum creatinine, increase in serum potassium,

juxtaglomerular (JG) hyperplasia in the kidney and focal erosions in the glandular stomach in

rats. All these changes were reversible after a 4-week recovery period and were considered to

be exaggerated pharmacological effects.

The amlodipine/valsartan/hydrochlorothiazide combination was not tested for genotoxicity or

carcinogenicity as there was no evidence of any interaction between these substances, which

have been on the market for a long time. However, amlodipine, valsartan and

hydrochlorothiazide have been tested individually for genotoxicity and carcinogenicity with

negative results.

Amlodipine

Reproductive toxicology

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged

duration of labour and decreased pup survival at dosages approximately 50 times greater than

the maximum recommended dosage for humans based on mg/kg.

Impairment of fertility

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and

females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum

recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male

rats were treated with amlodipine besilate for 30 days at a dose comparable with the human

dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were

found as well as decreases in sperm density and in the number of mature spermatids and

Sertoli cells. 

Carcinogenesis, mutagenesis

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated

to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of

carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum

recommended clinical dose of 10 mg on a mg/m2 basis) was close to the maximum tolerated

dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome

levels.

* Based on patient weight of 50 kg

Valsartan

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

In rats, maternally toxic doses (600 mg/kg/day) during the last days of gestation and lactation

led to lower survival, lower weight gain and delayed development (pinna detachment and earcanal

opening) in the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are

approximately 18 times the maximum recommended human dose on a mg/m2 basis

(calculations assume an oral dose of 320 mg/day and a 60-kg patient).

In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused

in rats a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and

evidence of changes in renal haemodynamics (slightly raised plasma urea, and renal tubular

hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are

approximately 6 and 18 times the maximum recommended human dose on a mg/m2 basis

(calculations assume an oral dose of 320 mg/day and a 60-kg patient).

In marmosets at similar doses, the changes were similar though more severe, particularly in

the kidney where the changes developed to a nephropathy which included raised urea and

creatinine.

Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes

were considered to be caused by the pharmacological action of valsartan which produces

prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in

humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any

relevance.

Microcrystalline Cellulose

Crospovidone

Colloidal Silicone Dioxide

Magnesium Stearate

Opadry

Ferric Oxide Yellow

Carnauba Wax

Not applicable.

2 years.

Store below 30°C.

 

Five Aluminum / Aluminum blisters of 6 tablets each, packed in a printed carton with folded leaflet.

No special requirements.