ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Imprida HCT 5 mg/160 mg/12.5 mg film-coated tablets
2.
Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate), 160 mg of valsartan,
and 12.5 mg of hydrochlorothiazide.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet)
White, ovaloid, biconvex tablets with bevelled edge, debossed “NVR” on one side and “VCL” on the
other side.
4.
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 Imprida HCT is one tablet per day, to be taken preferably in the morning.
Before switching to Imprida HCT patients should be controlled on stable doses of the
monocomponents taken at the same time. The dose of Imprida HCT should be based on the doses of
the individual components of the combination at the time of switching.
The maximum recommended dose of Imprida HCT is 10 mg/320 mg/25 mg.
Special populations
Renal impairment
Due to the hydrochlorothiazide component, Imprida HCT is contraindicated in patients with severe
renal impairment (creatinine clearance <30 ml/min) (see sections 4.3 and 5.2). No dosage adjustment
is required for patients with mild to moderate renal impairment. Monitoring of potassium levels and
creatinine is advised in patients with moderate renal impairment.
Hepatic impairment
Due to the hydrochlorothiazide and valsartan components, Imprida HCT 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 Imprida HCT
is not suitable in this group of patients (see sections 4.3, 4.4 and 5.2).
2
Heart failure and coronary artery disease
There is limited experience with the use of Imprida HCT, 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 Imprida HCT, 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 Imprida HCT, 10 mg/320 mg/25 mg, since available data in this
patient population are limited.
Paediatric population
There is no relevant use of Imprida HCT in the paediatric population (patients below age 18 years) for
the indication of essential hypertension.
Method of administration
Imprida HCT 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 sulfonamides, 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 m
2
), anuria and patients undergoing dialysis.
−
Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.
Sodium- and/or volume-depleted patients
Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with
the maximum dose of Imprida HCT (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 patients with an activated renin-
angiotensin system (such as volume- and/or salt-depleted patients receiving high doses of diuretics)
who are receiving angiotensin II receptor antagonists (AIIRAs), symptomatic hypotension may occur.
Correction of this condition prior to administration of Imprida HCT or close medical supervision at the
start of treatment is recommended.
If excessive hypotension occurs with Imprida HCT, 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 Imprida HCT, 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.
3
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
Hypokalaemia has been reported under treatment with thiazide diuretics including
hydrochlorothiazide.
Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with
hyponatraemia and hypochloroaemic alkalosis. Thiazides, including hydrochlorothiazide, increase the
urinary excretion of magnesium, which may result in hypomagnesaemia. Calcium excretion is
decreased by thiazide diuretics. This may result in hypercalcaemia.
Renal impairment
No dosage adjustment of Imprida HCT is required for patients with mild to moderate renal impairment
(GFR >30 ml/min/1.73 m
2
). Periodic monitoring of serum potassium, creatinine and uric acid is
recommended when Imprida HCT is used in patients with renal impairment.
Renal artery stenosis
No data are available on the use of Imprida HCT in patients with unilateral or bilateral renal artery
stenosis or stenosis to a solitary kidney.
Kidney transplantation
To date there is no experience of the safe use of Imprida HCT in patients who have had a recent
kidney transplantation.
Hepatic impairment
Valsartan is mostly eliminated unchanged via the bile, whereas amlodipine is extensively metabolised
by the liver. In patients with mild to moderate hepatic impairment without cholestasis, the maximum
recommended dose is 80 mg valsartan, and therefore, Imprida HCT is not suitable in this group of
patients (see sections 4.2, 4.3 and 5.2).
Heart failure and coronary artery disease
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
angiotensin-converting enzyme (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.
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.
Caution is advised in patients with heart failure and coronary artery disease, particularly at the
maximum dose of Imprida HCT, 10 mg/320 mg/25 mg, since available data in these patient
populations is limited.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with all other vasodilators, special caution is indicated in patients with aortic or mitral stenosis, or
obstructive hypertrophic cardiomyopathy.
4
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, Imprida HCT 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.
Thiazides may reduce urinary calcium excretion and cause intermittant and slight elevation of serum
calcium in the absence of known disorders of calcium metabolism. 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 Imprida HCT, 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.
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 Imprida HCT, 10 mg/320 mg/25 mg, since available data in this
patient population are limited.
No formal interaction studies with other medicinal products were performed with Imprida HCT. 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 Imprida HCT may increase the hypotensive effect of
other antihypertensive agents.
5
Concomitant use not recommended
Imprida
HCT
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.
Caution required with concomitant use
Imprida
HCT
individual
component
Known interactions
with the following
agents
Effect of the interaction with other medicinal products
Amlodipine
CYP3A4 inhibitors
(i.e. ketoconazole,
itraconazole, ritonavir)
A study in elderly patients has shown that diltiazem
inhibits the metabolism of amlodipine, probably via
CYP3A4 (plasma concentration increases by
approximately 50% and the effect of amlodipine is
increased). The possibility that more potent inhibitors of
CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may
increase the plasma concentration of amlodipine to a
greater extent than diltiazem cannot be excluded.
CYP3A4 inducers
(anticonvulsant agents
[e.g. carbamazepine,
phenobarbital,
phenytoin,
fosphenytoin,
primidone], rifampicin,
Hypericum perforatum
[St. John’s wort])
Co-administration may lead to reduced plasma
concentrations of amlodipine. Clinical monitoring is
indicated, with possible dosage adjustment of amlodipine
during the treatment with the inducer and after its
withdrawal.
Valsartan
and HCT
Non-steroidal anti-
inflammatory
medicines (NSAIDs),
including selective
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 Imprida HCT 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.
6
Medicinal products
affected by serum
potassium disturbances
Periodic monitoring of serum potassium and ECG is
recommended when a hydrochlorothiazide containing
product is administered with agents affected by serum
potassium disturbances (e.g. digitalis glycosides,
antiarrhythmics) and the following agents that induce
torsades de pointes (which include some antiarrhythmics),
hypokalaemia being a predisposing factor for
torsades de
pointes
.
- 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,
methadone)
- Others (e.g. bepridil, cisapride, diphemanil,
erythromycin i.v., halofantrin, ketanserin, mizolastin,
pentamidine, moxifloxacine, terfenadine, vincamine
i.v.)
HCT
Alcohol, anaesthetics
and sedatives
Potentiation of orthostatic hypotension may occur.
Amantadine
Thiazides, including hydrochlorothiazide, may increase
the risk of adverse reactions caused by amantadine.
Anticholinergic agents
(e.g. atropine,
biperiden)
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.
Antidiabetic medicinal
products
(e.g. insulin
and oral antidiabetic
agents)
It may prove necessary to readjust the dosage of insulin
and of oral antidiabetic agents.
−
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.
Carbamazepine
Patients receiving hydrochlorothiazide concomitantly with
carbamazepine may develop hyponatraemia. Such patients
should therefore be advised about the possibility of
hyponatraemic reactions, and should be monitored
accordingly.
Cholestyramine and
cholestipol resins
Absorption of thiazide diuretics, including
hydrochlorothiazide, is decreased by cholestyramine and
other anionic exchange resins.
Ciclosporin
Concomitant treatment with ciclosporin may increase the
risk of hyperuricaemia and gout-type complications.
Cytotoxic agents
(e.g.
cyclophosphamide,
methotrexate)
Thiazides, including hydrochlorothiazide, may reduce the
renal excretion of cytotoxic agents (e.g.
cyclophosphamide, methotrexate) and potentiate their
myelosuppressive effects.
7
Digitalis glycosides
Thiazide-induced hypokalaemia or hypomagnesaemia may
occur as unwanted 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.
Medicinal products
affecting potassium
(kaliuretic diuretics,
corticosteroids,
laxatives, ACTH,
amphotericin,
carbenoxolone,
penicillin G, salicylic
acid derivatives)
The hypokalaemic effect of hydrochlorothiazide may be
increased by kaliuretic diuretics, corticosteroids, laxatives,
adrenocorticotropic hormone (ACTH), amphotericin,
carbenoxolone, penicillin G and salicylic acid derivatives.
If these medicinal products are to be prescribed with the
amlodipine /valsartan /hydrochlorothiazide combination,
monitoring of potassium plasma levels is advised.
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.
Pressor amines
(e.g.
noradrenaline,
adrenaline)
The effect of pressor amines may be decreased.
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.
No interaction
Imprida
HCT
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 Imprida HCT (see
interactions related to HCT).
8
Pregnancy
Amlodipine
Data on a limited number of pregnancies indicate no adverse effects of amlodipine and other calcium
receptor antagonists on the health of the foetus. However, there may be a risk of prolonged delivery.
Valsartan
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 and may be associated with other adverse reactions that have occurred in adults.
Amlodipine/valsartan/hydrochlorothiazide
There is no experience on the use of Imprida HCT in pregnant women. Based on the existing data with
the components, the use of Imprida HCT is not recommended during first trimester and contra-
indicated 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 breast-feeding.
Hydrochlorothiazide is excreted into breast milk. Therefore, the use of Imprida HCT is not
recommended during breast-feeding. Alternative treatments with better established safety profiles
during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. When driving
vehicles or using machines it should be taken into account that occasionally dizziness or weariness
may occur.
9
The safety profile of Imprida HCT presented below is based on clinical studies performed with
Imprida HCT and the known safety profile of the individual components amlodipine, valsartan and
hydrochlorothiazide.
Information on Imprida HCT
The safety of Imprida HCT 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 Imprida HCT 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 Imprida HCT 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
Imprida HCT (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
Imprida
HCT
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
--
Very rare
Not known
Rare
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
--
--
Uncommon
Hypochloraemic alkalosis
--
--
--
Very rare
Hypokalaemia
Common
--
--
Common
Hypomagnesaemia
--
--
--
Uncommon
Hyponatraemia
Uncommon
--
--
Uncommon
Psychiatric
disorders
Depression
--
--
--
Rare
Insomnia/sleep disturbances Uncommon Uncommon
--
Rare
Mood swings
--
Uncommon
--
10
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
--
--
Eye disorders
Visual disturbance
Uncommon Uncommon
--
Uncommon
Ear and labyrinth
disorders
Tinnitus
--
Uncommon
--
--
Vertigo
Uncommon
--
Uncommon
--
Cardiac disorders
Palpitations
--
Common
--
--
Tachycardia
Uncommon
--
--
--
Arrhythmia (including
bradycardia, ventricular
tachycardia, and atrial
fibrillation)
--
Very rare
--
Rare
Myocardial infarction
--
Very rare
--
--
Vascular
disorders
Flushing
--
Common
--
--
Hypotension
Common
Uncommon
--
--
Orthostatic hypotension
Uncommon
--
--
Uncommon
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
--
--
--
Uncommon
Diarrhoea
Uncommon Uncommon
--
Rare
Dry mouth
Uncommon Uncommon
--
--
Dyspepsia
Common
Uncommon
--
--
Gastritis
--
Very rare
--
--
Gingival hyperplasia
--
Very rare
--
--
Nausea
Uncommon
Common
--
Uncommon
Pancreatitis
--
Very rare
--
Very rare
Vomiting
Uncommon Uncommon
--
Uncommon
11
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
--
--
Exanthema
--
Uncommon
--
--
Hyperhidrosis
Uncommon Uncommon
--
--
Photosensitivity reaction*
--
--
--
Rare
Pruritus
Uncommon Uncommon Not known
--
Purpura
--
Uncommon
--
Rare
Rash
--
Uncommon Not known Uncommon
Skin discoloration
--
Uncommon
--
--
Urticaria
--
Very rare
--
Uncommon
Vasculitis necrotising and
toxic epidermal necrolysis
--
--
--
Very rare
Musculoskeletal
and connective
tissue disorders
Arthralgia
--
Uncommon
--
--
Back pain
Uncommon Uncommon
--
--
Joint swelling
Uncommon
--
--
--
Muscle spasm
Uncommon Uncommon
--
--
Muscular weakness
Uncommon
--
--
--
Myalgia
Uncommon Uncommon Not known
--
Pain in extremity
Uncommon
--
--
--
Renal and
urinary disorders
Elevation of serum
creatinine
Uncommon
--
Not known
--
Micturition disorder
Uncommon
Nocturia
--
Uncommon
--
--
Pollakiuria
Common
Uncommon
Renal failure acute
Uncommon
--
--
--
Renal failure and
impairment
--
--
Not known
Rare
Reproductive
system and breast
disorders
Erectile dysfunction
Uncommon Uncommon
--
Uncommon
Gynaecomastia
Uncommon
--
--
General disorders
and
administration
site conditions
Abasia, gait disturbance
Uncommon
--
--
--
Asthenia
Uncommon Uncommon
--
--
Discomfort, malaise
Uncommon Uncommon
--
--
Fatigue
Common
Common
Uncommon
--
Non cardiac chest pain
Uncommon Uncommon
--
--
Oedema
Common
Common
--
--
Pain
--
Uncommon
--
--
12
Investigations
Lipids increased
--
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
Symptoms
There is no experience of overdose with Imprida HCT. The major symptom of overdose with valsartan
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 Imprida HCT 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
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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II antagonists, plain (valsartan), combinations with
dihydropyridine derivatives (amlodipine) and thiazide diuretics (hydrochlorothiazide), ATC code:
C09DX01 valsartan, amlodipine and hydrochlorothiazide.
13
Imprida HCT 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
Imprida HCT 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
Imprida HCT, 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 Imprida HCT 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 Imprida HCT. Statistically greater proportions of patients achieved
blood pressure control (<140/90 mmHg) with Imprida HCT (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 Imprida HCT 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.
Valsartan
Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively
on the receptor subtype AT
1
, which is responsible for the known actions of angiotensin II.
14
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
Imprida HCT in all subsets of the paediatric population in essential hypertension. See section 4.2 for
information on paediatric use.
5.2 Pharmacokinetic properties
Linearity
Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics.
Amlodipine/valsartan/hydrochlorothiazide
Following oral administration of Imprida HCT 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
Imprida HCT 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 (C
max
) 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.
15
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 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 (T
max
about
2 hours).The increase in mean AUC is linear and dose proportional in the therapeutic range. There is
no change change in the kinetics of hydrochlorothiazide on repeated dosing and accumulation is
minimal when dosed once daily. Concomitant administration with food has been reported to both
increase and decrease the systemic availability of hydrochlorothiazide compared with the fasted state.
The magnitude of these effects is small and has little clinical importance. Absolute bioavailability of
hydrochlorothiazide is 60-80 % 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 1.8 times the level in plasma.
Biotransformation:
Hydrochlorothiazide is eliminated as unchanged drug.
Elimination:
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.
The terminal half-life is 6-15 hours.
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.
16
Patients with mild to moderate renal impairment may therefore receive the usual initial dose (see
sections 4.2 and 4.4).
Hepatic impairment
Patients with hepatic insufficiency 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). Caution should be exercised in patients with liver disease (see section 4.2).
5.3 Preclinical safety data
In a variety of preclinical safety studies conducted in several animal species with amlodipine,
valsartan, hydrochlorothiazide, valsartan/hydrochlorothiazide, amlodipine/valsartan and
amlodipine/valsartan/hydrochlorothiazide (Imprida HCT), there was no evidence of systemic or target
organ toxicity that would adversely affect the development of Imprida HCT 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.
6.
6.1 List of excipients
Tablet core
Cellulose microcrystalline
Crospovidone
Silica, colloidal anhydrous
Magnesium stearate
Coating
Hypromellose
Titanium dioxide (E171)
Macrogol 4000
Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months
17
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PVC/PVDC blisters. One blister contains 7, 10 or 14 film-coated tablets.
Pack sizes: 14, 28, 30, 56, 90, 98 or 280 film-coated tablets.
Multipacks of 280 tablets, comprising 20
cartons, each containing 14
tablets.
PVC/PVDC perforated unit dose blisters for hospital use:
Pack sizes: 56, 98 or 280 film-coated tablets
Multipacks of 280 tablets, comprising 4 cartons, each containing 70 tablets.
Not all pack sizes or strengths may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/09/570/001-012
9.
15.10.2009
18
1.
Imprida HCT 10 mg/160 mg/12.5 mg film-coated tablets
2.
Each film-coated tablet contains 10 mg of amlodipine (as amlodipine besylate), 160 mg of valsartan,
and 12.5 mg of hydrochlorothiazide.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet)
Pale yellow, ovaloid, biconvex tablets with bevelled edge, debossed “NVR” on one side and “VDL”
on the other side.
4.
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 Imprida HCT is one tablet per day, to be taken preferably in the morning.
Before switching to Imprida HCT patients should be controlled on stable doses of the
monocomponents taken at the same time. The dose of Imprida HCT should be based on the doses of
the individual components of the combination at the time of switching.
The maximum recommended dose of Imprida HCT is 10 mg/320 mg/25 mg.
Special populations
Renal impairment
Due to the hydrochlorothiazide component, Imprida HCT is contraindicated in patients with severe
renal impairment (creatinine clearance <30 ml/min) (see sections 4.3 and 5.2). No dosage adjustment
is required for patients with mild to moderate renal impairment. Monitoring of potassium levels and
creatinine is advised in patients with moderate renal impairment.
Hepatic impairment
Due to the hydrochlorothiazide and valsartan components, Imprida HCT 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 Imprida HCT
is not suitable in this group of patients (see sections 4.3, 4.4 and 5.2).
19
Heart failure and coronary artery disease
There is limited experience with the use of Imprida HCT, 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 Imprida HCT, 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 Imprida HCT, 10 mg/320 mg/25 mg, since available data in this
patient population are limited.
Paediatric population
There is no relevant use of Imprida HCT in the paediatric population (patients below age 18 years) for
the indication of essential hypertension.
Method of administration
Imprida HCT 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 sulfonamides, 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 m
2
), anuria and patients undergoing dialysis.
−
Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.
Sodium- and/or volume-depleted patients
Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with
the maximum dose of Imprida HCT (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 patients with an activated renin-
angiotensin system (such as volume- and/or salt-depleted patients receiving high doses of diuretics)
who are receiving angiotensin II receptor antagonists (AIIRAs), symptomatic hypotension may occur.
Correction of this condition prior to administration of Imprida HCT or close medical supervision at the
start of treatment is recommended.
If excessive hypotension occurs with Imprida HCT, 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 Imprida HCT, 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.
20
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
Hypokalaemia has been reported under treatment with thiazide diuretics including
hydrochlorothiazide.
Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with
hyponatraemia and hypochloroaemic alkalosis. Thiazides, including hydrochlorothiazide, increase the
urinary excretion of magnesium, which may result in hypomagnesaemia. Calcium excretion is
decreased by thiazide diuretics. This may result in hypercalcaemia.
Renal impairment
No dosage adjustment of Imprida HCT is required for patients with mild to moderate renal impairment
(GFR >30 ml/min/1.73 m
2
). Periodic monitoring of serum potassium, creatinine and uric acid is
recommended when Imprida HCT is used in patients with renal impairment.
Renal artery stenosis
No data are available on the use of Imprida HCT in patients with unilateral or bilateral renal artery
stenosis or stenosis to a solitary kidney.
Kidney transplantation
To date there is no experience of the safe use of Imprida HCT in patients who have had a recent
kidney transplantation.
Hepatic impairment
Valsartan is mostly eliminated unchanged via the bile, whereas amlodipine is extensively metabolised
by the liver. In patients with mild to moderate hepatic impairment without cholestasis, the maximum
recommended dose is 80 mg valsartan, and therefore, Imprida HCT is not suitable in this group of
patients (see sections 4.2, 4.3 and 5.2).
Heart failure and coronary artery disease
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
angiotensin-converting enzyme (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.
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.
Caution is advised in patients with heart failure and coronary artery disease, particularly at the
maximum dose of Imprida HCT, 10 mg/320 mg/25 mg, since available data in these patient
populations is limited.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with all other vasodilators, special caution is indicated in patients with aortic or mitral stenosis, or
obstructive hypertrophic cardiomyopathy.
21
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, Imprida HCT 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.
Thiazides may reduce urinary calcium excretion and cause intermittant and slight elevation of serum
calcium in the absence of known disorders of calcium metabolism. 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 Imprida HCT, 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.
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 Imprida HCT, 10 mg/320 mg/25 mg, since available data in this
patient population are limited.
No formal interaction studies with other medicinal products were performed with Imprida HCT. 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 Imprida HCT may increase the hypotensive effect of
other antihypertensive agents.
22
Concomitant use not recommended
Imprida
HCT
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.
Caution required with concomitant use
Imprida
HCT
individual
component
Known interactions
with the following
agents
Effect of the interaction with other medicinal products
Amlodipine
CYP3A4 inhibitors
(i.e. ketoconazole,
itraconazole, ritonavir)
A study in elderly patients has shown that diltiazem
inhibits the metabolism of amlodipine, probably via
CYP3A4 (plasma concentration increases by
approximately 50% and the effect of amlodipine is
increased). The possibility that more potent inhibitors of
CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may
increase the plasma concentration of amlodipine to a
greater extent than diltiazem cannot be excluded.
CYP3A4 inducers
(anticonvulsant agents
[e.g. carbamazepine,
phenobarbital,
phenytoin,
fosphenytoin,
primidone], rifampicin,
Hypericum perforatum
[St. John’s wort])
Co-administration may lead to reduced plasma
concentrations of amlodipine. Clinical monitoring is
indicated, with possible dosage adjustment of amlodipine
during the treatment with the inducer and after its
withdrawal.
Valsartan
and HCT
Non-steroidal anti-
inflammatory
medicines (NSAIDs),
including selective
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 Imprida HCT 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.
23
Medicinal products
affected by serum
potassium disturbances
Periodic monitoring of serum potassium and ECG is
recommended when a hydrochlorothiazide containing
product is administered with agents affected by serum
potassium disturbances (e.g. digitalis glycosides,
antiarrhythmics) and the following agents that induce
torsades de pointes (which include some antiarrhythmics),
hypokalaemia being a predisposing factor for
torsades de
pointes
.
- 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,
methadone)
- Others (e.g. bepridil, cisapride, diphemanil,
erythromycin i.v., halofantrin, ketanserin, mizolastin,
pentamidine, moxifloxacine, terfenadine, vincamine
i.v.)
HCT
Alcohol, anaesthetics
and sedatives
Potentiation of orthostatic hypotension may occur.
Amantadine
Thiazides, including hydrochlorothiazide, may increase
the risk of adverse reactions caused by amantadine.
Anticholinergic agents
(e.g. atropine,
biperiden)
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.
Antidiabetic medicinal
products
(e.g. insulin
and oral antidiabetic
agents)
It may prove necessary to readjust the dosage of insulin
and of oral antidiabetic agents.
−
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.
Carbamazepine
Patients receiving hydrochlorothiazide concomitantly with
carbamazepine may develop hyponatraemia. Such patients
should therefore be advised about the possibility of
hyponatraemic reactions, and should be monitored
accordingly.
Cholestyramine and
cholestipol resins
Absorption of thiazide diuretics, including
hydrochlorothiazide, is decreased by cholestyramine and
other anionic exchange resins.
Ciclosporin
Concomitant treatment with ciclosporin may increase the
risk of hyperuricaemia and gout-type complications.
Cytotoxic agents
(e.g.
cyclophosphamide,
methotrexate)
Thiazides, including hydrochlorothiazide, may reduce the
renal excretion of cytotoxic agents (e.g.
cyclophosphamide, methotrexate) and potentiate their
myelosuppressive effects.
24
Digitalis glycosides
Thiazide-induced hypokalaemia or hypomagnesaemia may
occur as unwanted 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.
Medicinal products
affecting potassium
(kaliuretic diuretics,
corticosteroids,
laxatives, ACTH,
amphotericin,
carbenoxolone,
penicillin G, salicylic
acid derivatives)
The hypokalaemic effect of hydrochlorothiazide may be
increased by kaliuretic diuretics, corticosteroids, laxatives,
adrenocorticotropic hormone (ACTH), amphotericin,
carbenoxolone, penicillin G and salicylic acid derivatives.
If these medicinal products are to be prescribed with the
amlodipine /valsartan /hydrochlorothiazide combination,
monitoring of potassium plasma levels is advised.
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.
Pressor amines
(e.g.
noradrenaline,
adrenaline)
The effect of pressor amines may be decreased.
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.
No interaction
Imprida
HCT
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 Imprida HCT (see
interactions related to HCT).
25
Pregnancy
Amlodipine
Data on a limited number of pregnancies indicate no adverse effects of amlodipine and other calcium
receptor antagonists on the health of the foetus. However, there may be a risk of prolonged delivery.
Valsartan
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 and may be associated with other adverse reactions that have occurred in adults.
Amlodipine/valsartan/hydrochlorothiazide
There is no experience on the use of Imprida HCT in pregnant women. Based on the existing data with
the components, the use of Imprida HCT is not recommended during first trimester and contra-
indicated 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 breast-feeding.
Hydrochlorothiazide is excreted into breast milk. Therefore, the use of Imprida HCT is not
recommended during breast-feeding. Alternative treatments with better established safety profiles
during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. When driving
vehicles or using machines it should be taken into account that occasionally dizziness or weariness
may occur.
26
The safety profile of Imprida HCT presented below is based on clinical studies performed with
Imprida HCT and the known safety profile of the individual components amlodipine, valsartan and
hydrochlorothiazide.
Information on Imprida HCT
The safety of Imprida HCT 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 Imprida HCT 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 Imprida HCT 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
Imprida HCT (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
Imprida
HCT
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
--
Very rare
Not known
Rare
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
--
--
Uncommon
Hypochloraemic alkalosis
--
--
--
Very rare
Hypokalaemia
Common
--
--
Common
Hypomagnesaemia
--
--
--
Uncommon
Hyponatraemia
Uncommon
--
--
Uncommon
Psychiatric
disorders
Depression
--
--
--
Rare
Insomnia/sleep disturbances Uncommon Uncommon
--
Rare
Mood swings
--
Uncommon
--
27
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
--
--
Eye disorders
Visual disturbance
Uncommon Uncommon
--
Uncommon
Ear and labyrinth
disorders
Tinnitus
--
Uncommon
--
--
Vertigo
Uncommon
--
Uncommon
--
Cardiac disorders
Palpitations
--
Common
--
--
Tachycardia
Uncommon
--
--
--
Arrhythmia (including
bradycardia, ventricular
tachycardia, and atrial
fibrillation)
--
Very rare
--
Rare
Myocardial infarction
--
Very rare
--
--
Vascular
disorders
Flushing
--
Common
--
--
Hypotension
Common
Uncommon
--
--
Orthostatic hypotension
Uncommon
--
--
Uncommon
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
--
--
--
Uncommon
Diarrhoea
Uncommon Uncommon
--
Rare
Dry mouth
Uncommon Uncommon
--
--
Dyspepsia
Common
Uncommon
--
--
Gastritis
--
Very rare
--
--
Gingival hyperplasia
--
Very rare
--
--
Nausea
Uncommon
Common
--
Uncommon
Pancreatitis
--
Very rare
--
Very rare
Vomiting
Uncommon Uncommon
--
Uncommon
28
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
--
--
Exanthema
--
Uncommon
--
--
Hyperhidrosis
Uncommon Uncommon
--
--
Photosensitivity reaction*
--
--
--
Rare
Pruritus
Uncommon Uncommon Not known
--
Purpura
--
Uncommon
--
Rare
Rash
--
Uncommon Not known Uncommon
Skin discoloration
--
Uncommon
--
--
Urticaria
--
Very rare
--
Uncommon
Vasculitis necrotising and
toxic epidermal necrolysis
--
--
--
Very rare
Musculoskeletal
and connective
tissue disorders
Arthralgia
--
Uncommon
--
--
Back pain
Uncommon Uncommon
--
--
Joint swelling
Uncommon
--
--
--
Muscle spasm
Uncommon Uncommon
--
--
Muscular weakness
Uncommon
--
--
--
Myalgia
Uncommon Uncommon Not known
--
Pain in extremity
Uncommon
--
--
--
Renal and
urinary disorders
Elevation of serum
creatinine
Uncommon
--
Not known
--
Micturition disorder
Uncommon
Nocturia
--
Uncommon
--
--
Pollakiuria
Common
Uncommon
Renal failure acute
Uncommon
--
--
--
Renal failure and
impairment
--
--
Not known
Rare
Reproductive
system and breast
disorders
Erectile dysfunction
Uncommon Uncommon
--
Uncommon
Gynaecomastia
Uncommon
--
--
General disorders
and
administration
site conditions
Abasia, gait disturbance
Uncommon
--
--
--
Asthenia
Uncommon Uncommon
--
--
Discomfort, malaise
Uncommon Uncommon
--
--
Fatigue
Common
Common
Uncommon
--
Non cardiac chest pain
Uncommon Uncommon
--
--
Oedema
Common
Common
--
--
Pain
--
Uncommon
--
--
29
Investigations
Lipids increased
--
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
Symptoms
There is no experience of overdose with Imprida HCT. The major symptom of overdose with valsartan
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 Imprida HCT 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
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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II antagonists, plain (valsartan), combinations with
dihydropyridine derivatives (amlodipine) and thiazide diuretics (hydrochlorothiazide), ATC code:
C09DX01 valsartan, amlodipine and hydrochlorothiazide.
30
Imprida HCT 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
Imprida HCT 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
Imprida HCT, 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 Imprida HCT 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 Imprida HCT. Statistically greater proportions of patients achieved
blood pressure control (<140/90 mmHg) with Imprida HCT (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 Imprida HCT 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.
Valsartan
Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively
on the receptor subtype AT
1
, which is responsible for the known actions of angiotensin II.
31
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
Imprida HCT in all subsets of the paediatric population in essential hypertension. See section 4.2 for
information on paediatric use.
5.2 Pharmacokinetic properties
Linearity
Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics.
Amlodipine/valsartan/hydrochlorothiazide
Following oral administration of Imprida HCT 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
Imprida HCT 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 (C
max
) 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.
32
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 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 (T
max
about
2 hours).The increase in mean AUC is linear and dose proportional in the therapeutic range. There is
no change change in the kinetics of hydrochlorothiazide on repeated dosing and accumulation is
minimal when dosed once daily. Concomitant administration with food has been reported to both
increase and decrease the systemic availability of hydrochlorothiazide compared with the fasted state.
The magnitude of these effects is small and has little clinical importance. Absolute bioavailability of
hydrochlorothiazide is 60-80 % 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 1.8 times the level in plasma.
Biotransformation:
Hydrochlorothiazide is eliminated as unchanged drug.
Elimination:
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.
The terminal half-life is 6-15 hours.
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.
33
Patients with mild to moderate renal impairment may therefore receive the usual initial dose (see
sections 4.2 and 4.4).
Hepatic impairment
Patients with hepatic insufficiency 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). Caution should be exercised in patients with liver disease (see section 4.2).
5.3 Preclinical safety data
In a variety of preclinical safety studies conducted in several animal species with amlodipine,
valsartan, hydrochlorothiazide, valsartan/hydrochlorothiazide, amlodipine/valsartan and
amlodipine/valsartan/hydrochlorothiazide (Imprida HCT), there was no evidence of systemic or target
organ toxicity that would adversely affect the development of Imprida HCT 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.
6.
6.1 List of excipients
Tablet core
Cellulose microcrystalline
Crospovidone
Silica, colloidal anhydrous
Magnesium stearate
Coating
Hypromellose
Macrogol 4000
Talc
Titanium dioxide (E171)
Iron oxide, yellow (E172)
Iron oxide, red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months
34
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PVC/PVDC blisters. One blister contains 7, 10 or 14 film-coated tablets.
Pack sizes: 14, 28, 30, 56, 90, 98 or 280 film-coated tablets.
Multipacks of 280 tablets, comprising 20
cartons, each containing 14
tablets.
PVC/PVDC perforated unit dose blisters for hospital use:
Pack sizes: 56, 98 or 280 film-coated tablets
Multipacks of 280 tablets, comprising 4 cartons, each containing 70 tablets.
Not all pack sizes or strengths may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/09/570/013-024
9.
15.10.2009
35
1.
Imprida HCT 5 mg/160 mg/25 mg film-coated tablets
2.
Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate), 160 mg of valsartan,
and 25 mg of hydrochlorothiazide.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet)
Yellow, ovaloid, biconvex tablets with bevelled edge, debossed “NVR” on one side and “VEL” on the
other side.
4.
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 Imprida HCT is one tablet per day, to be taken preferably in the morning.
Before switching to Imprida HCT patients should be controlled on stable doses of the
monocomponents taken at the same time. The dose of Imprida HCT should be based on the doses of
the individual components of the combination at the time of switching.
The maximum recommended dose of Imprida HCT is 10 mg/320 mg/25 mg.
Special populations
Renal impairment
Due to the hydrochlorothiazide component, Imprida HCT is contraindicated in patients with severe
renal impairment (creatinine clearance <30 ml/min) (see sections 4.3 and 5.2). No dosage adjustment
is required for patients with mild to moderate renal impairment. Monitoring of potassium levels and
creatinine is advised in patients with moderate renal impairment.
Hepatic impairment
Due to the hydrochlorothiazide and valsartan components, Imprida HCT 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 Imprida HCT
is not suitable in this group of patients (see sections 4.3, 4.4 and 5.2).
36
Heart failure and coronary artery disease
There is limited experience with the use of Imprida HCT, 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 Imprida HCT, 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 Imprida HCT, 10 mg/320 mg/25 mg, since available data in this
patient population are limited.
Paediatric population
There is no relevant use of Imprida HCT in the paediatric population (patients below age 18 years) for
the indication of essential hypertension.
Method of administration
Imprida HCT 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 sulfonamides, 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 m
2
), anuria and patients undergoing dialysis.
−
Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.
Sodium- and/or volume-depleted patients
Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with
the maximum dose of Imprida HCT (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 patients with an activated renin-
angiotensin system (such as volume- and/or salt-depleted patients receiving high doses of diuretics)
who are receiving angiotensin II receptor antagonists (AIIRAs), symptomatic hypotension may occur.
Correction of this condition prior to administration of Imprida HCT or close medical supervision at the
start of treatment is recommended.
If excessive hypotension occurs with Imprida HCT, 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 Imprida HCT, 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.
37
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
Hypokalaemia has been reported under treatment with thiazide diuretics including
hydrochlorothiazide.
Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with
hyponatraemia and hypochloroaemic alkalosis. Thiazides, including hydrochlorothiazide, increase the
urinary excretion of magnesium, which may result in hypomagnesaemia. Calcium excretion is
decreased by thiazide diuretics. This may result in hypercalcaemia.
Renal impairment
No dosage adjustment of Imprida HCT is required for patients with mild to moderate renal impairment
(GFR >30 ml/min/1.73 m
2
). Periodic monitoring of serum potassium, creatinine and uric acid is
recommended when Imprida HCT is used in patients with renal impairment.
Renal artery stenosis
No data are available on the use of Imprida HCT in patients with unilateral or bilateral renal artery
stenosis or stenosis to a solitary kidney.
Kidney transplantation
To date there is no experience of the safe use of Imprida HCT in patients who have had a recent
kidney transplantation.
Hepatic impairment
Valsartan is mostly eliminated unchanged via the bile, whereas amlodipine is extensively metabolised
by the liver. In patients with mild to moderate hepatic impairment without cholestasis, the maximum
recommended dose is 80 mg valsartan, and therefore, Imprida HCT is not suitable in this group of
patients (see sections 4.2, 4.3 and 5.2).
Heart failure and coronary artery disease
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
angiotensin-converting enzyme (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.
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.
Caution is advised in patients with heart failure and coronary artery disease, particularly at the
maximum dose of Imprida HCT, 10 mg/320 mg/25 mg, since available data in these patient
populations is limited.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with all other vasodilators, special caution is indicated in patients with aortic or mitral stenosis, or
obstructive hypertrophic cardiomyopathy.
38
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, Imprida HCT 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.
Thiazides may reduce urinary calcium excretion and cause intermittant and slight elevation of serum
calcium in the absence of known disorders of calcium metabolism. 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 Imprida HCT, 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.
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 Imprida HCT, 10 mg/320 mg/25 mg, since available data in this
patient population are limited.
No formal interaction studies with other medicinal products were performed with Imprida HCT. 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 Imprida HCT may increase the hypotensive effect of
other antihypertensive agents.
39
Concomitant use not recommended
Imprida
HCT
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.
Caution required with concomitant use
Imprida
HCT
individual
component
Known interactions
with the following
agents
Effect of the interaction with other medicinal products
Amlodipine
CYP3A4 inhibitors
(i.e. ketoconazole,
itraconazole, ritonavir)
A study in elderly patients has shown that diltiazem
inhibits the metabolism of amlodipine, probably via
CYP3A4 (plasma concentration increases by
approximately 50% and the effect of amlodipine is
increased). The possibility that more potent inhibitors of
CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may
increase the plasma concentration of amlodipine to a
greater extent than diltiazem cannot be excluded.
CYP3A4 inducers
(anticonvulsant agents
[e.g. carbamazepine,
phenobarbital,
phenytoin,
fosphenytoin,
primidone], rifampicin,
Hypericum perforatum
[St. John’s wort])
Co-administration may lead to reduced plasma
concentrations of amlodipine. Clinical monitoring is
indicated, with possible dosage adjustment of amlodipine
during the treatment with the inducer and after its
withdrawal.
Valsartan
and HCT
Non-steroidal anti-
inflammatory
medicines (NSAIDs),
including selective
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 Imprida HCT 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.
40
Medicinal products
affected by serum
potassium disturbances
Periodic monitoring of serum potassium and ECG is
recommended when a hydrochlorothiazide containing
product is administered with agents affected by serum
potassium disturbances (e.g. digitalis glycosides,
antiarrhythmics) and the following agents that induce
torsades de pointes (which include some antiarrhythmics),
hypokalaemia being a predisposing factor for
torsades de
pointes
.
- 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,
methadone)
- Others (e.g. bepridil, cisapride, diphemanil,
erythromycin i.v., halofantrin, ketanserin, mizolastin,
pentamidine, moxifloxacine, terfenadine, vincamine
i.v.)
HCT
Alcohol, anaesthetics
and sedatives
Potentiation of orthostatic hypotension may occur.
Amantadine
Thiazides, including hydrochlorothiazide, may increase
the risk of adverse reactions caused by amantadine.
Anticholinergic agents
(e.g. atropine,
biperiden)
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.
Antidiabetic medicinal
products
(e.g. insulin
and oral antidiabetic
agents)
It may prove necessary to readjust the dosage of insulin
and of oral antidiabetic agents.
−
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.
Carbamazepine
Patients receiving hydrochlorothiazide concomitantly with
carbamazepine may develop hyponatraemia. Such patients
should therefore be advised about the possibility of
hyponatraemic reactions, and should be monitored
accordingly.
Cholestyramine and
cholestipol resins
Absorption of thiazide diuretics, including
hydrochlorothiazide, is decreased by cholestyramine and
other anionic exchange resins.
Ciclosporin
Concomitant treatment with ciclosporin may increase the
risk of hyperuricaemia and gout-type complications.
Cytotoxic agents
(e.g.
cyclophosphamide,
methotrexate)
Thiazides, including hydrochlorothiazide, may reduce the
renal excretion of cytotoxic agents (e.g.
cyclophosphamide, methotrexate) and potentiate their
myelosuppressive effects.
41
Digitalis glycosides
Thiazide-induced hypokalaemia or hypomagnesaemia may
occur as unwanted 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.
Medicinal products
affecting potassium
(kaliuretic diuretics,
corticosteroids,
laxatives, ACTH,
amphotericin,
carbenoxolone,
penicillin G, salicylic
acid derivatives)
The hypokalaemic effect of hydrochlorothiazide may be
increased by kaliuretic diuretics, corticosteroids, laxatives,
adrenocorticotropic hormone (ACTH), amphotericin,
carbenoxolone, penicillin G and salicylic acid derivatives.
If these medicinal products are to be prescribed with the
amlodipine /valsartan /hydrochlorothiazide combination,
monitoring of potassium plasma levels is advised.
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.
Pressor amines
(e.g.
noradrenaline,
adrenaline)
The effect of pressor amines may be decreased.
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.
No interaction
Imprida
HCT
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 Imprida HCT (see
interactions related to HCT).
42
Pregnancy
Amlodipine
Data on a limited number of pregnancies indicate no adverse effects of amlodipine and other calcium
receptor antagonists on the health of the foetus. However, there may be a risk of prolonged delivery.
Valsartan
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 and may be associated with other adverse reactions that have occurred in adults.
Amlodipine/valsartan/hydrochlorothiazide
There is no experience on the use of Imprida HCT in pregnant women. Based on the existing data with
the components, the use of Imprida HCT is not recommended during first trimester and contra-
indicated 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 breast-feeding.
Hydrochlorothiazide is excreted into breast milk. Therefore, the use of Imprida HCT is not
recommended during breast-feeding. Alternative treatments with better established safety profiles
during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. When driving
vehicles or using machines it should be taken into account that occasionally dizziness or weariness
may occur.
43
The safety profile of Imprida HCT presented below is based on clinical studies performed with
Imprida HCT and the known safety profile of the individual components amlodipine, valsartan and
hydrochlorothiazide.
Information on Imprida HCT
The safety of Imprida HCT 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 Imprida HCT 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 Imprida HCT 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
Imprida HCT (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
Imprida
HCT
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
--
Very rare
Not known
Rare
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
--
--
Uncommon
Hypochloraemic alkalosis
--
--
--
Very rare
Hypokalaemia
Common
--
--
Common
Hypomagnesaemia
--
--
--
Uncommon
Hyponatraemia
Uncommon
--
--
Uncommon
Psychiatric
disorders
Depression
--
--
--
Rare
Insomnia/sleep disturbances Uncommon Uncommon
--
Rare
Mood swings
--
Uncommon
--
44
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
--
--
Eye disorders
Visual disturbance
Uncommon Uncommon
--
Uncommon
Ear and labyrinth
disorders
Tinnitus
--
Uncommon
--
--
Vertigo
Uncommon
--
Uncommon
--
Cardiac disorders
Palpitations
--
Common
--
--
Tachycardia
Uncommon
--
--
--
Arrhythmia (including
bradycardia, ventricular
tachycardia, and atrial
fibrillation)
--
Very rare
--
Rare
Myocardial infarction
--
Very rare
--
--
Vascular
disorders
Flushing
--
Common
--
--
Hypotension
Common
Uncommon
--
--
Orthostatic hypotension
Uncommon
--
--
Uncommon
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
--
--
--
Uncommon
Diarrhoea
Uncommon Uncommon
--
Rare
Dry mouth
Uncommon Uncommon
--
--
Dyspepsia
Common
Uncommon
--
--
Gastritis
--
Very rare
--
--
Gingival hyperplasia
--
Very rare
--
--
Nausea
Uncommon
Common
--
Uncommon
Pancreatitis
--
Very rare
--
Very rare
Vomiting
Uncommon Uncommon
--
Uncommon
45
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
--
--
Exanthema
--
Uncommon
--
--
Hyperhidrosis
Uncommon Uncommon
--
--
Photosensitivity reaction*
--
--
--
Rare
Pruritus
Uncommon Uncommon Not known
--
Purpura
--
Uncommon
--
Rare
Rash
--
Uncommon Not known Uncommon
Skin discoloration
--
Uncommon
--
--
Urticaria
--
Very rare
--
Uncommon
Vasculitis necrotising and
toxic epidermal necrolysis
--
--
--
Very rare
Musculoskeletal
and connective
tissue disorders
Arthralgia
--
Uncommon
--
--
Back pain
Uncommon Uncommon
--
--
Joint swelling
Uncommon
--
--
--
Muscle spasm
Uncommon Uncommon
--
--
Muscular weakness
Uncommon
--
--
--
Myalgia
Uncommon Uncommon Not known
--
Pain in extremity
Uncommon
--
--
--
Renal and
urinary disorders
Elevation of serum
creatinine
Uncommon
--
Not known
--
Micturition disorder
Uncommon
Nocturia
--
Uncommon
--
--
Pollakiuria
Common
Uncommon
Renal failure acute
Uncommon
--
--
--
Renal failure and
impairment
--
--
Not known
Rare
Reproductive
system and breast
disorders
Erectile dysfunction
Uncommon Uncommon
--
Uncommon
Gynaecomastia
Uncommon
--
--
General disorders
and
administration
site conditions
Abasia, gait disturbance
Uncommon
--
--
--
Asthenia
Uncommon Uncommon
--
--
Discomfort, malaise
Uncommon Uncommon
--
--
Fatigue
Common
Common
Uncommon
--
Non cardiac chest pain
Uncommon Uncommon
--
--
Oedema
Common
Common
--
--
Pain
--
Uncommon
--
--
46
Investigations
Lipids increased
--
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
Symptoms
There is no experience of overdose with Imprida HCT. The major symptom of overdose with valsartan
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 Imprida HCT 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
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.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II antagonists, plain (valsartan), combinations with
dihydropyridine derivatives (amlodipine) and thiazide diuretics (hydrochlorothiazide), ATC code:
C09DX01 valsartan, amlodipine and hydrochlorothiazide.
47
Imprida HCT 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
Imprida HCT 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
Imprida HCT, 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 Imprida HCT 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 Imprida HCT. Statistically greater proportions of patients achieved
blood pressure control (<140/90 mmHg) with Imprida HCT (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 Imprida HCT 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.
Valsartan
Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively
on the receptor subtype AT
1
, which is responsible for the known actions of angiotensin II.
48
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
Imprida HCT in all subsets of the paediatric population in essential hypertension. See section 4.2 for
information on paediatric use.
5.2 Pharmacokinetic properties
Linearity
Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics.
Amlodipine/valsartan/hydrochlorothiazide
Following oral administration of Imprida HCT 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
Imprida HCT 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 (C
max
) 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.
49
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 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 (T
max
about
2 hours).The increase in mean AUC is linear and dose proportional in the therapeutic range. There is
no change change in the kinetics of hydrochlorothiazide on repeated dosing and accumulation is
minimal when dosed once daily. Concomitant administration with food has been reported to both
increase and decrease the systemic availability of hydrochlorothiazide compared with the fasted state.
The magnitude of these effects is small and has little clinical importance. Absolute bioavailability of
hydrochlorothiazide is 60-80 % 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 1.8 times the level in plasma.
Biotransformation:
Hydrochlorothiazide is eliminated as unchanged drug.
Elimination:
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.
The terminal half-life is 6-15 hours.
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.
50
Patients with mild to moderate renal impairment may therefore receive the usual initial dose (see
sections 4.2 and 4.4).
Hepatic impairment
Patients with hepatic insufficiency 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). Caution should be exercised in patients with liver disease (see section 4.2).
5.3 Preclinical safety data
In a variety of preclinical safety studies conducted in several animal species with amlodipine,
valsartan, hydrochlorothiazide, valsartan/hydrochlorothiazide, amlodipine/valsartan and
amlodipine/valsartan/hydrochlorothiazide (Imprida HCT), there was no evidence of systemic or target
organ toxicity that would adversely affect the development of Imprida HCT 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.
6.
6.1 List of excipients
Tablet core
Cellulose microcrystalline
Crospovidone
Silica, colloidal anhydrous
Magnesium stearate
Coating
Hypromellose
Macrogol 4000
Talc
Titanium dioxide (E171)
Iron oxide, yellow (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
18 months
51
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PVC/PVDC blisters. One blister contains 7, 10 or 14 film-coated tablets.
Pack sizes: 14, 28, 30, 56, 90, 98 or 280 film-coated tablets.
Multipacks of 280 tablets, comprising 20
cartons, each containing 14
tablets.
PVC/PVDC perforated unit dose blisters for hospital use:
Pack sizes: 56, 98 or 280 film-coated tablets
Multipacks of 280 tablets, comprising 4 cartons, each containing 70 tablets.
Not all pack sizes or strengths may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/09/570/025-036
9.
15.10.2009
52
1.
FURTHER INFORMATION
What Imprida HCT contains
−
The active substances of Imprida HCT are amlodipine (as amlodipine besylate), valsartan and
hydrochlorothiazide.
−
Imprida HCT 10 mg/320 mg/25 mg film-coated tablets: Each film-coated tablet contains 10 mg
amlodipine (as amlodipine besylate), 320 mg valsartan, and 25 mg hydrochlorothiazide. The
other ingredients are cellulose microcrystalline; crospovidone; silica, colloidal anhydrous,
magnesium stearate, hypromellose, macrogol 4000, talc, yellow iron oxide (E172).
What Imprida HCT looks like and contents of the pack
−
Imprida HCT 10 mg/320 mg/25 mg film-coated tablets are brown-yellow, oval tablets with
“NVR” on one side and “VFL” on the other side.
Imprida HCT is available in packs containing 14, 28, 30, 56, 90, 98 or 280 film-coated tablets, in
multipacks of 280 tablets (comprising 4 cartons, each containing 70 tablets, or 20 cartons, each
containing 14 tablets), and in hospital packs containing 56, 98 or 280 tablets in single unit blisters. Not
all pack sizes may be available in your country.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
Manufacturer
Novartis Pharma GmbH
Roonstraße 25
D-90429 Nuremberg
Germany
164
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
България
Novartis Pharma Services Inc.
Тел.: +359 2 976 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Eesti
Novartis Pharma Services Inc.
Tel: +372 66 30 810
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
Ελλάδα
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
Lacer, S.A.
Tel: +34 93 446 53 00
Portugal
Novartis Farma - Produtos Farmacêuticos, S.A.
Tel: +351 21 000 8600
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439
Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 9 61 33 22 11
Κύπρος
Δημητριάδης και Παπαέλληνας Λτδ
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
165
Latvija
Novartis Pharma Services Inc.
Tel: +371 67 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
166
Source: European Medicines Agency
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