Summary of medicine characteristics - Imprida HCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
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. PHARMACEUTICAL FORM
Film-coated tablet (tablet)
White, ovaloid, biconvex tablets with bevelled edge, debossed “NVR” on one s other side.
on the
4. CLINICAL PARTICULARS4.1 Therapeutic indications
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.
4.2 Posology and method of administration
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 maximu
mended dose of Imprida HCT is 10 mg/320 mg/25 mg.
Special populations
Renal impairment
No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.4 and 5.2). Due to the hydrochlorothiazide component, Imprida HCT is contraindicated for use in patients with anuria (see section 4.3) and in patients with severe renal impairment (glomerular filtration rate (GFR) <30 ml/min/1.73 m2) (see sections 4.3, 4.4 and 5.2).
Hepatic impairment
Due to the valsartan component, 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).
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.
4.3 Contraindications
-
– Hypersensitivity to the active substances, to other sulphonamide derivatives, to dihydropyridine derivatives, or to any of the excipients.
-
– Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
-
– Hepatic impairment, biliary cirrhosis or cholestasis.
-
– Severe renal impairment (GFR <30 ml/min/1.73 m2), anuria and patients undergoing dialysis.
-
– Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.
4.4 Special warnings and precautions for use
4.4 Special warnings and precautions for useSodium- 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 sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur after initiation of treatment with Imprida HCT. Imprida HCT should be used only after correction of any pre-existing sodium and/or volume depletion.
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.
Valsartan
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) is not recommended. Monitoring of potassium should be undertaken as appropriate.
Hydrochlorothiazide
Treatment with Imprida HCT should only start after correction of hypokalaemia and any coexisting hypomagnesaemia. Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate preexisting hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced potassium loss, for example salt-losing nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalaemia develops during hydrochlorothiazide therapy, Imprida HCT should be discontinued until stable correction of the potassium balance.
Thiazide diuretics can precipitate new onset hyponatraemia and hypochloroaemic alkalosis or exacerbate pre-existing hyponatraemia. Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed. Treatment with hydrochlorothiazide should only be started after correction of pre-existing hyponatraemia. In case severe or rapid hyponatraemia develops during Imprida HCT therapy, the treatment should be discontinued until normalisation of natraemia.
All patients receiving thiazide diuretics should be periodically monitored for imbalances in electrolytes, particularly potassium, sodium and magnesium.
Renal impairment
Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. When Imprida HCT is used in patients with renal impairment periodic monitoring of serum electrolytes (including potassium), creatinine and uric acid serum levels is recommended. Imprida HCT is contraindicated in patients with severe renal impairment, anuria or undergoing dialysis (see section 4.3).
No dosage adjustment of Imprida HCT is required for patients with mild to moderate renal impairment (GFR >30 ml/min/1.73 m2).
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 transplantatio n^^
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.
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.
Due to the hydrochlorothiazide component, Imprida HCT is contraindicated in symptomatic hyperuricaemia. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricaemia as well as precipitate gout in susceptible patients.
Thiazides reduce urinary calcium excretion and may cause intermittant and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Imprida HCT is contraindicated in patients with hypercalcaemia and should only be used after correction of any pre-existing hypercalcaemia. Imprida HCT should be discontinued if hypercalcaemia develops during treatment. Serum levels of calcium should be periodically monitored during treatment with thiazides. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment with 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.
Acute angle-closure glaucoma
Hydrochlorothiazide, a sulphonamide, has been associated with an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to a week of treatment initiation.
Untreated acute-angle closure glaucoma can lead to permanent vision loss.
The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history of sulphonamide or penicillin allergy.
General
Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
Elderly (age 65 years or over)
Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of Imprida HCT, 10 mg/320 mg/25 mg, since available data in this patient population are limited.
4.5 Interaction with other medicinal products and other forms of interaction
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.
Concomitant use not recommended
| Imprida HCT individual component | Known interactions with the following agents |
In monotherapy with valsartan, no interactions of clinical significance have been found with the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine,
HCT with the following
individual agents
component ____________________
Valsartan Others
(cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin,
hydrochlorothiazide, amlodipine, glibenclamide)
glibenclamide.
Some of these substances could interact with the
hydrochlorothiazide component of Imprida HCT (see /^.interactions related to HCT). ______________________________
Amlodipine Others In clinical interaction studies, amlodipine did not affect
the pharmacokinetics of atorvastatin, digoxin, warfarin or ciclosporin.
4.6 Fertility, pregnancy and lactation
4.6 Fertility, pregnancy and lactationPregnancy
Amlodipine
The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses (see section 5.3). Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.
Valsartan ____________________________________________________________________________________
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).
4.7 Effects on ability to drive and use machines
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.
4.8 Undesirable effects
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: >1/1,000to <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, sometimes with purpura | — | Very rare | Not known | Rare | |
| Aplastic anaemia | — | — | — | Not known |
| Immune system disorders | Hypersensitivity | -- | Very rare | Not known | Very rare |
| Metabolism and nutrition disorders | Anorexia | Uncommon | — | — | — |
| Hypercalcaemia | Uncommon | — | — | Rare | |
| Hyperglycaemia | — | Very rare | — | Rare | |
| Hyperlipidaemia | Uncommon | — | — | — | |
| Hyperuricaemia | Uncommon | — | — | Common | |
| Hypochloraemic alkalosis | — | — | — | Very rare | |
| Hypokalaemia | Common | — | — | Very common | |
| Hypomagnesaemia | — | — | — | Common | |
| Hyponatraemia | Uncommon | — | — | Common | |
| Worsening of diabetic metabolic state | — | — | — | Rare | |
| Psychiatric disorders | Depression | — | — | Rare | |
| Insomnia/sleep disturbances | Uncommon | Uncommon | < | Rare | |
| Mood swings | — | Uncommon | -- | ||
| Nervous system disorders | Coordination abnormal | Uncommon | -- c | V -- | — |
| Dizziness | Common | Common | — | Rare | |
| Dizziness postural, dizziness exertional | Uncommon | — | — | — | |
| Dysgeusia | Uncommon | Uncommon | — | — | |
| Extrapyramidal syndrome | – n | Not known | — | — | |
| Headache | Common | Common | — | Rare | |
| Hypertonia | T | Very rare | — | — | |
| Lethargy | Uncommon | — | — | — | |
| Paraesthesia | Uncommon | Uncommon | — | Rare | |
| Peripheral neuropathy, neuropathy | ^Uncommon | Very rare | — | — | |
| Somnolence | Uncommon | Common | — | — | |
| Syncope | Uncommon | Uncommon | — | — | |
| Tremor | — | Uncommon | — | — | |
| Eye disorders | Acute angle-closure glaucoma | — | — | — | Not known |
| Visual impairment | Uncommon | Uncommon | — | Rare | |
| Ear and labyrinth disorders | Tinnitus | — | Uncommon | — | — |
| V er tigo | Uncommon | — | Uncommon | — | |
| Cardiac disorders | Palpitations | — | Common | — | — |
| Tachycardia | Uncommon | — | — | — | |
| Arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation) | — | Very rare | — | Rare | |
| Myocardial infarction | — | Very rare | — | — | |
| Vascular disorders | Flushing | — | Common | — | — |
| Hypotension | Common | Uncommon | — | — | |
| Orthostatic hypotension | Uncommon | — | — | Common | |
| Phlebitis, thrombophlebitis | Uncommon | — | — | — | |
| Vasculitis | — | Very rare | Not known | — |
| Respiratory, thoracic and mediastinal disorders | Cough | Uncommon | Very rare | Uncommon | ■■ |
| Dyspnoea | Uncommon | Uncommon | — | — | |
| Respiratory distress, pulmonary oedema, pneumonitis | — | — | — | Very rare | |
| Rhinitis | — | Uncommon | — | — | |
| Throat irritation | Uncommon | — | — | — | |
| Gastrointestinal disorders | Abdominal discomfort, abdominal pain upper | Uncommon | Common | Uncommon | Rare |
| Breath odour | Uncommon | — | — | — | |
| Change of bowel habit | — | Uncommon | — | — | |
| Constipation | — | — | — | Rare | |
| Decreased appetite | — | — | — | Common | |
| Diarrhoea | Uncommon | Uncommon | — | Rare | |
| Dry mouth | Uncommon | Uncommon | — | — | |
| Dyspepsia | Common | Uncommon | ■■ | — | |
| Gastritis | — | Very rare | ■■> | — | |
| Gingival hyperplasia | — | Very rare | ■■ | — | |
| Nausea | Uncommon |
| r -■ | Common | |
| Pancreatitis | — | Very rare | — | Very rare | |
| Vomiting | Uncommon | Uncommon | — | Common | |
| Hepatobiliary disorders | Hepatic enzyme elevation, including increase of serum bilirubin | — e | Very rare &— | Not known | — |
| Hepatitis | -- | Very rare | — | — | |
| Intrahepatic cholestasis, jaundice | Very rare | — | Rare | ||
| Skin and subcutaneous tissue disorders | Alopecia | — | Uncommon | — | |
| Angioedema | — | Very rare | Not known | — | |
| Cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus | -- | — | — | Very rare | |
| Erythema multiforme | — | Very rare | — | Not known | |
| Exanthema | — | Uncommon | — | — | |
| Hyperhidrosis | Uncommon | Uncommon | — | — | |
| Photosensitivity reaction* | — | — | — | Rare | |
| Pruritus | Uncommon | Uncommon | Not known | — | |
| Purpura | — | Uncommon | — | Rare | |
| Rash | — | Uncommon | Not known | Common | |
| Skin discoloration | — | Uncommon | — | — | |
| Urticaria and other forms of rash | — | Very rare | — | Common | |
| Vasculitis necrotising and toxic epidermal necrolysis | — | — | — | Very rare | |
| Musculoskeletal and connective tissue disorders | Arthralgia | — | Uncommon | — | — |
| Back pain | Uncommon | Uncommon | — | — | |
| Joint swelling | Uncommon | — | — | — | |
| Muscle spasm | Uncommon | Uncommon | — | Not known | |
| Muscular weakness | Uncommon | — | — | — | |
| Myalgia | Uncommon | Uncommon | Not known | — | |
| Pain in extremity | Uncommon | — | — | — |
| Renal and urinary disorders | Elevation of serum creatinine | Uncommon | -- | Not known | -- |
| Micturition disorder | Uncommon | ||||
| Nocturia | — | Uncommon | — | — | |
| Pollakiuria | Common | Uncommon | |||
| Renal dysfunction | — | — | — | Not known | |
| Renal failure acute | Uncommon | — | — | Not known | |
| Renal failure and impairment | — | — | Not known | Rare | |
| Reproductive system and breast disorders | Impotence | Uncommon | Uncommon | — | Common |
| Gynaecomastia | Uncommon | — | — | ||
| General disorders and administration site conditions | Abasia, gait disturbance | Uncommon | — | — | — |
| Asthenia | Uncommon | Uncommon | — | Not known | |
| Discomfort, malaise | Uncommon | Uncommon | — | — | |
| Fatigue | Common | Common | Uncommon | — | |
| Non cardiac chest pain | Uncommon | Uncommon | -- | — | |
| Oedema | Common | Common | -- | — | |
| Pain | — | Uncommon | V -- | — | |
| Pyrexia | — | — | — | Not known | |
| Investigations | Lipids increased | — | Very common | ||
| Blood urea nitrogen increased | Uncommon | – – | — | — | |
| Blood uric acid increased | — Uncomm on | -- | — | ||
| Glycosuria | Rare | ||||
| Serum potassium decreased | Uncommon | — | — | — | |
| Serum potassium increased | — | — | Not known | — | |
| Weight increase | ^Uncommon | Uncommon | — | — | |
| Weight decrease | -- | Uncommon | — | — |
See section 4.4 Photosensitivi
4.9 Overdose
Symptoms
There is no experience of overdose with Imprida HCT. The major symptom of overdose with
valsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine may result in excessive peripheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged systemic hypotension, including shock with fatal outcome, have been reported with amlodipine.
Treatment
Amlodipine/Valsartan/Hydrochlorothiazide
Clinically significant hypotension due to 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
Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and hypovolaemia resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasms and or accentuate arrhythmia associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.
The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.
5. PHARMACOLOGICAL PROPERTIES5.1 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.
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
1.5/19.5 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 AT1, which is responsible for the known actions of angiotensin II.
Administration of valsartan to patients with hypertension results in a drop in blood pressure without affecting pulse rate.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs
within 2 hours, and the peak drop in blood pressure is achieved within 4–6 hours. The antihypertensive effect persists over 24 hours after administration. During repeated administration, the maximum reduction in blood pressure with any dose is generally attained within 2–4 weeks.
Hydrochlorothiazide
The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter perhaps by competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly, by this diuretic action, reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium.
The European Medicines Agency has waived the obligation to submit the results of studies with 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 (Cmax) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without food.
Distribution: The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94–97%), mainly serum albumin.
Biotransformation: Valsartan is not transformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.
Hydrochlorothiazide
Absorption: The absorption of hydrochlorothiazide, after an oral dose, is rapid (Tmax about 2 hours). The increase in mean AUC is linear and dose proportional in the therapeutic range.
The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance. Absolute bioavailability of hydrochlorothiazide is 70% after oral administration.
Distribution: The apparent volume of distribution is 4–8 l/kg. Circulating hydrochlorothiazide is bound to serum proteins (40–70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma.
Biotransformation: Hydrochlorothiazide is eliminated predominantly as unchanged compound.
Elimination: Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily. More than 95% of the absorbed dose is being excreted as unchanged compound in the urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule.
Special populations
Paediatric patients (age below 18 years)
No pharmacokinetic data are available in the paediatric population.
Elderly (age 65 years or over)
Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC) and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in the young, therefore caution is required when increasing the dosage.
Systemic exposure to valsartan is slightly elevated in the elderly as compared to the young, but this has not been shown to have any clinical significance.
Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
Since the three components are equally well tolerated in younger and elderly patients, normal dose regimens are recommended (see section 4.2).
Renal impairment
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation was seen between renal function and systemic exposure to valsartan.
Patients with mild to moderate renal impairment may therefore receive the usual initial dose (see sections 4.2 and 4.4).
In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with mild to moderate renal impairment, a 3-fold increase in hydrochlorothiazide AUC has been observed. In patients with severe renal impairment an 8-fold increase in AUC has been observed. Imprida HCT is contraindicated in patients with severe renal impairment, anuria or undergoing dialysis (see section 4.3).
Hepatic impairment
Patients with hepatic insuffici
ve decreased clearance of amlodipine with resulting increase of
approximately 40–60% in AUC. On average, in patients with mild to moderate chronic liver disease, exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers (matched by age, sex and weight). Due to the valsartan component, Imprida HCT is contraindicated in patients with hepatic impairment (see sections 4.2 and 4.3).
5.3 Preclinical safety data
Amlodipine/Valsartan/Hydrochlorothiazide
In a variety of preclinical safety studies conducted in several animal species with amlodipine, valsartan, hydrochlorothiazide, valsartan/hydrochlorothiazide, amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide (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.
Amlodipine
Reproductive toxicology
Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.
Impairment of fertility
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.
Carcinogenesis, mutagenesis
Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.
Mutagenicity studies revealed no drug related effects at
e gene or chromosome levels.
* Based on patient weight of 50 kg
mans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
In rats, maternally toxic doses (600 mg/kg/day) during the last days of gestation and lactation led to
lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).
In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal haemodynamics (slightly raised plasma urea, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).
In marmosets at similar doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy which included raised urea and creatinine.
Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
6. PHARMACEUTICAL PARTICULARS6.1 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
2 years
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 contain
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. MARKETING AUTHORISATION HOLDER
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/09/570/001–012
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
15.10.2009