4.1. Therapeutic indications

Treatment of essential hypertension.

Amlodipine / Valsartan is indicated in adults whose blood pressure is not adequately controlled on amlodipine or valsartan monotherapy.

4.2. Posology and method of administration

Posology

The recommended dose of Amlodipine / Valsartan is one tablet per day.

Amlodipine / Valsartan 5 mg / 80 mg film-coated tablets may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg or valsartan 80 mg alone.

Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed-dose combination may be considered.

For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may be switched to Amlodipine / Valsartan containing the same component doses.

Renal impairment

There are no available clinical data in severely renally impaired patients.

No dosage adjustment is required for patients with mild to moderate renal impairment. Monitoring of potassium levels and creatinine is advised in moderate renal impairment.

Hepatic impairment

Amlodipine / Valsartan is contraindicated in patients with severe hepatic impairment (see section 4.3).

Caution should be exercised when administering Amlodipine / Valsartan to patients with hepatic impairment or biliary obstructive disorders (see section 4.4). In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan. Amlodipine dosage recommendations have not been established in patients with mild to moderate hepatic impairment.

When switching eligible hypertensive patients (see section 4.1) with hepatic impairment to amlodipine or Amlodipine / Valsartan, the lowest available dose of amlodipine monotherapy or of the amlodipine component, respectively, should be used.

Elderly (age ≥ 65 years)

In elderly patients, caution is required when increasing the dosage. When switching eligible elderly hypertensive patients (see section 4.1) to amlodipine or Amlodipine / Valsartan, the lowest available dose of amlodipine monotherapy or of the amlodipine component, respectively, should be used.

Paediatric population

The safety and efficacy of Amlodipine / Valsartan in children aged < 18 years have not been established. No data are available.

Method of administration

Oral use.

It is recommended to take Amlodipine / Valsartan with some water. Amlodipine / Valsartan can be used with or without food.

4.3. Contraindications

- Hypersensitivity to the active substances, to dihydropyridine derivatives or to any of the excipients listed in section 6.1.

- Severe hepatic impairment, biliary cirrhosis or cholestasis.

- Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

- Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

- Severe hypotension.

- Shock (including cardiogenic shock).

- Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy and high grade aortic stenosis).

- Haemodynamically unstable heart failure after acute myocardial infarction.

4.4. Special warnings and precautions for use

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

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).

Sodium- and/or volume-depleted patients

Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with amlodipine/valsartan in placebo-controlled studies. 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 receptor blockers, symptomatic hypotension may occur. Correction of this condition prior to administration of amlodipine/valsartan or close medical supervision at the start of treatment is recommended.

If hypotension occurs with amlodipine/valsartan, 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.

Hyperkalaemia

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels.

Renal artery stenosis

Amlodipine/valsartan should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine may increase in such patients.

Kidney transplantation

To date there is no experience of the safe use of amlodipine/valsartan in patients who have had a recent kidney transplantation.

Hepatic impairment

Valsartan is mostly eliminated unchanged via the bile. The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Particular caution should be exercised when administering amlodipine/valsartan to patients with mild to moderate hepatic impairment or biliary obstructive disorders.

In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan.

Renal impairment

No dosage adjustment of amlodipine/valsartan is required for patients with mild to moderate renal impairment (GFR > 30 ml/min/1.73 m2). Monitoring of potassium levels and creatinine is advised in moderate renal impairment.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with the AIIRA valsartan as their renin-angiotensin system is affected by the primary disease.

Angioedema

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue, has been reported in patients treated with valsartan. Some of these patients previously experienced angioedema with other medicinal products, including ACE inhibitors. Amlodipine/valsartan should be discontinued immediately in patients who develop angioedema and should not be re-administered.

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including valsartan (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Heart failure / post-myocardial infarction

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.

In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Heart Association classification) III and IV heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Aortic and mitral valve stenosis

As with all other vasodilators, special caution is indicated in patients suffering from mitral stenosis or significant aortic stenosis that is not high grade.

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

There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE inhibitors, ARBs or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Amlodipine/valsartan has not been studied in any patient population other than hypertension.

Excipients

Amlodipine/Valsartan 5 mg / 80 mg film-coated tablets: This medicinal product contains 9.25 mg sorbitol in each tablet.

The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet; that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Interactions common to the combination

No drug-drug interaction studies have been performed with amlodipine/valsartan and other medicinal products.

To be taken into account with concomitant use

Other antihypertensive agents

Commonly used antihypertensive agents (e.g. α-blockers, diuretics) and other medicinal products which may cause hypotensive adverse effects (e.g. tricyclic antidepressants, α-blockers for treatment of benign prostate hyperplasia) may increase the antihypertensive effect of the combination.

Interactions linked to amlodipine

Concomitant use not recommended

Grapefruit or grapefruit juice

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients, resulting in increased blood pressure lowering effects.

Caution required with concomitant use

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure resulting in an increased risk of hypotension. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Close clinical observation of patients is recommended and dose adjustment may thus be required.

CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, Hypericum perforatum)

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).

Simvastatin

Co-administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose of simvastatin to 20 mg daily in patients on amlodipine.

Dantrolene (infusion)

In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Tacrolimus

There is a risk of increased tacrolimus blood levels when co administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

To be taken into account with concomitant use

Others

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or ciclosporin.

Interactions linked to valsartan

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors or AIIRAs, including valsartan. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use. If a diuretic is also used, the risk of lithium toxicity may presumably be increased further with amlodipine/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 to be prescribed in combination with valsartan, monitoring of potassium plasma levels is advised.

Caution required with concomitant use

Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs

When AIIRAs are administered simultaneously with NSAIDs attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of 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.

Inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir)

The results of an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and of the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.

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

Clinical trial data have shown that dual blockade of the RAAS through the combined use of ACE inhibitors, ARBs or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Others

In monotherapy with valsartan, no interactions of clinical significance have been found with the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipine, glibenclamide.

4.6. Fertility, pregnancy and lactation

Pregnancy

Amlodipine

The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses (see section 5.3). Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.

Valsartan

The use of 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 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 AIIRA 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).

Breast-feeding

Amlodipine

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

Amlodipine/valsartan

No information is available regarding the use of amlodipine/valsartan during breast-feeding, therefore amlodipine/valsartan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a new-born or preterm infant.

Fertility

There are no clinical studies on fertility with amlodipine/valsartan.

Valsartan

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6-times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).

Amlodipine

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Patients taking amlodipine/valsartan and driving vehicles or using machines should take into account that dizziness or weariness may occasionally occur.

Amlodipine can have mild or moderate influence on the ability to drive and use machines. If patients taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired.

4.8. Undesirable effects

Summary of the safety profile

The safety of amlodipine/valsartan has been evaluated in five controlled clinical studies with 5,175 patients; 2,613 of whom received valsartan in combination with amlodipine. The following adverse reactions were found to be the most frequently occurring or the most significant or severe: nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, oedema, pitting oedema, facial oedema, oedema peripheral, fatigue, flushing, asthenia and hot flush.

Tabulated list of adverse reactions

Adverse reactions have been ranked under headings of frequency using the following convention: 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

Amlodipine/valsartan

Amlodipine

Valsartan

Infections and infestations

Nasopharyngitis

Common

–

–

Influenza

Common

–

–

Blood and lymphatic system disorders

Haemoglobin and in haematocrit decreased

–

–

Not known

Leukopenia

–

Very rare

–

Neutropenia

–

–

Not known

Thrombocytopenia, sometimes with purpura

–

Very rare

Not known

Immune system disorders

Hypersensitivity

Rare

Very rare

Not known

Metabolism and nutrition disorders

Hyperglycaemia

–

Very rare

–

Hyponatraemia

Uncommon

–

–

Psychiatric disorders

Depression

–

Uncommon

–

Anxiety

Rare

–

–

Insomnia / sleep disorders

–

Uncommon

–

Mood swings

–

Uncommon

–

Confusion

–

Rare

–

Nervous system disorders

Coordination abnormal

Uncommon

–

–

Dizziness

Uncommon

Common

–

Dizziness postural

Uncommon

–

–

Dysgeusia

–

Uncommon

–

Extrapyramidal disorder

–

Not known

–

Headache

Common

Common

–

Hypertonia

–

Very rare

–

Paraesthesia

Uncommon

Uncommon

–

Peripheral neuropathy, neuropathy

–

Very rare

–

Somnolence

Uncommon

Common

–

Syncope

–

Uncommon

–

Tremor

–

Uncommon

–

Hypoesthesia

–

Uncommon

–

Eye disorders

Visual disturbance

Rare

Uncommon

–

Visual impairment

Uncommon

Uncommon

–

Ear and labyrinth disorders

Tinnitus

Rare

Uncommon

–

Vertigo

Uncommon

–

Uncommon

Cardiac disorders

Palpitations

Uncommon

Common

–

Syncope

Rare

–

–

Tachycardia

Uncommon

–

–

Arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation)

–

Very rare

–

Myocardial infarction

–

Very rare

–

Vascular disorders

Flushing

–

Common

–

Hypotension

Rare

Uncommon

–

Orthostatic hypotension

Uncommon

–

–

Vasculitis

–

Very rare

Not known

Respiratory, thoracic and mediastinal disorders

Cough

Uncommon

Very rare

Uncommon

Dyspnoea

–

Uncommon

–

Pharyngolaryngeal pain

Uncommon

–

–

Rhinitis

–

Uncommon

–

Gastrointestinal disorders

Abdominal discomfort, abdominal pain upper

Uncommon

Common

Uncommon

Change of bowel habit

–

Uncommon

–

Constipation

Uncommon

–

–

Diarrhoea

Uncommon

Uncommon

–

Dry mouth

Uncommon

Uncommon

–

Dyspepsia

–

Uncommon

–

Gastritis

–

Very rare

–

Gingival hyperplasia

–

Very rare

–

Intestinal angioedema

–

–

Very rare

Nausea

Uncommon

Common

–

Pancreatitis

–

Very rare

–

Vomiting

–

Uncommon

–

Hepatobiliary disorders

Liver function test abnormal, including blood bilirubin increase

–

Very rare*

Not known

Hepatitis

–

Very rare

–

Intrahepatic cholestasis, jaundice

–

Very rare

–

Skin and subcutaneous tissue disorders

Alopecia

–

Uncommon

–

Angioedema

–

Very rare

Not known

Dermatitis bullous

–

–

Not known

Erythema

Uncommon

–

–

Erythema multiforme

–

Very rare

–

Exanthema

Rare

Uncommon

–

Hyperhidrosis

Rare

Uncommon

–

Photosensitivity reaction

–

Uncommon

–

Pruritus

Rare

Uncommon

Not known

Purpura

–

Uncommon

–

Rash

Uncommon

Uncommon

Not known

Skin discolouration

–

Uncommon

–

Urticaria and other forms of rash

–

Very rare

–

Exfoliative dermatitis

–

Very rare

–

Stevens-Johnson syndrome

–

Very rare

–

Quincke oedema

-

Very rare

-

Toxic epidermal necrolysis

–

Not known

–

Musculoskeletal and connective tissue disorders

Arthralgia

Uncommon

Uncommon

–

Back pain

Uncommon

Uncommon

–

Joint swelling

Uncommon

–

–

Muscle spasm

Rare

Uncommon

–

Myalgia

–

Uncommon

Not known

Ankle swelling

–

Common

–

Sensation of heaviness

Rare

–

–

Renal and urinary disorders

Blood creatinine increased

–

–

Not known

Micturition disorder

–

Uncommon

–

Nocturia

–

Uncommon

–

Pollakiuria

Rare

Uncommon

–

Polyuria

Rare

–

–

Renal failure and impairment

–

–

Not known

Reproductive system and breast disorders

Impotence

–

Uncommon

–

Erectile dysfunction

Rare

–

–

Gynaecomastia

–

Uncommon

–

General disorders and administration site conditions

Asthenia

Common

Uncommon

–

Discomfort, malaise

–

Uncommon

–

Fatigue

Common

Common

Uncommon

Facial oedema

Common

–

–

Flushing, hot flush

Common

–

–

Non cardiac chest pain

–

Uncommon

–

Oedema

Common

Common

–

Oedema peripheral

Common

–

–

Pain

–

Uncommon

–

Pitting oedema

Common

–

–

Investigations

Blood potassium increased

–

–

Not known

Weight increase

–

Uncommon

–

Weight decrease

–

Uncommon

–

* Mostly consistent with cholestasis.

Additional information on the combination

Peripheral oedema, a recognised side effect of amlodipine, was generally observed at a lower incidence in patients who received the amlodipine/valsartan combination than in those who received amlodipine alone. In double-blind, controlled clinical trials, the incidence of peripheral oedema by dose was as follows:

% of patients who experienced peripheral oedema

Valsartan (mg)

0

40

80

160

320

Amlodipine (mg)

0

3.0

5.5

2.4

1.6

0.9

2.5

8.0

2.3

5.4

2.4

3.9

5

3.1

4.8

2.3

2.1

2.4

10

10.3

NA

NA

9.0

9.5

The mean incidence of peripheral oedema evenly weighted across all doses was 5.1% with the amlodipine/valsartan combination.

Additional information on the individual components

Adverse reactions previously reported with one of the individual components (amlodipine or valsartan) may be potential adverse reactions with amlodipine/valsartan as well, even if not observed in clinical trials or during the post-marketing period.

Amlodipine

Common

Somnolence, dizziness, palpitations, abdominal pain, nausea, ankle swelling.

Uncommon

Insomnia, mood changes (including anxiety), depression, tremor, dysgeusia, syncope, hypoesthesia, visual disturbance (including diplopia), tinnitus, hypotension, dyspnoea, rhinitis, vomiting, dyspepsia, alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, exanthema, myalgia, muscle cramps, pain, micturition disorder, increased urinary frequency, impotence, gynaecomastia, chest pain, malaise, weight increase, weight decrease.

Rare

Confusion.

Very rare

Leukocytopenia, thrombocytopenia, allergic reactions, hyperglycaemia, hypertonia, peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival hyperplasia, hepatitis, jaundice, hepatic enzymes increased*, angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity.

Not known

Extrapyramidal disorder.

* mostly consistent with cholestasis

Valsartan

Not known

Decrease in haemoglobin, decrease in haematocrit, neutropenia, thrombocytopenia, increase of serum potassium, elevation of liver function values including increase of serum bilirubin, renal failure and impairment, elevation of serum creatinine, angioedema, myalgia, vasculitis, hypersensitivity including serum sickness.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

There is no experience of overdose with amlodipine/valsartan. 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 up to and including shock with fatal outcome have been reported with amlodipine.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Management

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. Clinically significant hypotension due to amlodipine/valsartan 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.

Both valsartan and amlodipine are unlikely to be removed by haemodialysis.