Valvasc 80 mg/160 mg Film-Coated Tablets

Treatment of mild to moderate essential hypertension in patients whose blood pressure is normalized with the individual components in the same doses as the proposed fixed dose combination of VALVASC.

Patients receiving valsartan and amlodipine from separate tablets may be switched to VALVASC containing the same component doses.

Posology
The recommended dose is one tablet per day (the 3 strengths are listed under section 2).

Special populations

Elderly
Normal dosage regimens are recommended.

Children and adolescents
VALVASC is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy (see section 4.4).

Renal impairment
No dosage adjustment is required for patients with mild to moderate renal impairment. In patients with severe renal impairment dosages may need to be reduced (see section 4.4).

Hepatic impairment
Caution should be exercised when administering VALVASC to patients with hepatic impairment or biliary obstructive disorders (see section 4.4 and 4.8).

Method of administration
Oral use. It is recommended to take VALVASC with some water.

• Hypersensitivity to amlodipine, valsartan, or to dihydropyridine derivatives, or to any of the inactive ingredients of VALVASC listed in section 6.1
• A history of angioedema related to previous therapy with ACE-inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines (see section 4.4)
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Severe renal function impairment (creatinine clearance less than 30 mL/min)
• Bilateral renal artery stenosis (see section 4.4)
• Renal artery stenosis in patients with a single kidney (see section 4.4)
• Aortic stenosis (see section 4.4)
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see sections 4.4 and 4.5)
• Concomitant use of fluoroquinolones with ACE-inhibitors/Angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (Creatinine Clearance u2264 30 mL/min) and in elderly patients (see sections 4.4 and 4.5)
• Porphyria
• Lithium therapy: Concomitant administration with VALVASC may lead to toxic blood concentrations of lithium (see section 4.5)
• The concomitant use of VALVASC with aliskiren-containing products is contraindicated (see sections 4.4 and 4.5)
• Severe hepatic impairment, biliary cirrhosis or cholestasis (see section 4.4)
• Severe hypotension (see section 4.4)
• Shock (including cardiogenic shock)
• Haemodynamically unstable heart failure or after an acute myocardial infarction (see section 4.4)
• Pregnancy and lactation (see section 4.6)

Should a woman become pregnant while receiving VALVASC, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see sections 4.3 and 4.6).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers (ARBs) or aliskiren may increase the risk of hypotension, hyperkalaemia and decreases renal function (including acute renal failure) (see section 4.5). Dual blockade of RAAS through the combined use of VALVASC and aliskiren is therefore contraindicated (see sections 4.3).

VALVASC should not be used concomitantly with aliskiren (see sections 4.3 and 4.5). ACE-inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Sodium- and/or volume-depleted patients
Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with VALVASC 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 VALVASC or close medical supervision at the start of treatment is recommended (see section 4.3).

If hypotension occurs with VALVASC, 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 medicine products that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels (see sections 4.3 and 4.5).

Renal artery stenosis
VALVASC 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 (see section 4.3).

Kidney transplantation
To date there is no experience of the safe use of VALVASC 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 (see section 4.3). Particular caution should be exercised when administering VALVASC 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 VALVASC is required for patients with mild to moderate renal impairment (GFR > 30 mL/min/1.73 mu00b2). Monitoring of potassium levels and creatinine is advised in moderate renal impairment.

Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist 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 medicines, including angiotensin-converting enzyme (ACE) inhibitors. VALVASC should be discontinued immediately in patients who develop angioedema and should not be re-administered (see section 4.3).

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 uraemia and 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 (see section 4.3).

In a long-term, placebo-controlled study 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 (see section 4.3).

Concomitant use of fluoroquinolones and ACE-inhibitors/Angiotensin receptor blockers
Concomitant use of fluoroquinolones and ACE-inhibitors/Angiotensin receptor blockers may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment and monitored during treatment with fluoroquinolones or ACE-inhibitors/angiotensin receptor blockers whether used separately and/or concomitantly.

Interactions common to the combination
To be taken into account with concomitant use

Other antihypertensive agents
Commonly used antihypertensive agents (e.g. alpha blockers, diuretics) and other medicine products which may cause hypotensive adverse effects (e.g. tricyclic antidepressants, alpha 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. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required. Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co-administered with clarithromycin.

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 medicine 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 require 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 angiotensin II receptor antagonists, including valsartan (see section 4.3). 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 VALVASC.

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels
If a medicine 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 drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective NSAIDs
When angiotensin II antagonists are administered simultaneously with NSAIDs attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists 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).

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.

Concomitant use of fluoroquinolones and ACE-inhibitors/Angiotensin receptor blockers
Concomitant use of fluoroquinolones and ACE-inhibitors/Angiotensin receptor blockers may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see sections 4.3 and 4.4).

Safety in pregnancy and lactation has not been established (see section 4.3). When pregnancy is planned or confirmed VALVASC should be discontinued.

Women of child-bearing potential/ Contraception in males and females
Women of child-bearing age should ensure effective contraception.

Pregnancy
VALVASC is contraindicated during pregnancy (see section 4.3). Medicines affecting the renin-angiotensin system, such as VALVASC, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women.

Breastfeeding
VALVASC is contraindicated during lactation (see section 4.3). 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 u2013 7 %, with a maximum of 15 %. The effect of amlodipine on infants is unknown.

Fertility
There are no clinical studies on fertility with amlodipine/valsartan e.g. VALVASC.

Dizziness or weariness may occasionally occur. This should be taken into account by patients taking VALVASC. 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.

System Organ Class Description Frequency Amlodipine/ valsartan Amlodipine Valsartan Infections and infestations Nasopharyngitis Frequent -- -- Influenza Frequent -- -- Blood and lymphatic system disorders Decrease in haemoglobin and in haematocrit -- -- Not known Leukopenia -- Less frequent -- Neutropenia -- -- Not known Thrombocytopenia, sometimes with purpura -- Less frequent Not known Immune system disorders Hypersensitivity Less frequent Less frequent Not known Metabolism and nutrition disorders Anorexia Less frequent -- -- Hypercalcaemia Less frequent -- -- Hyperglycaemia -- Less frequent -- Hyperlipidaemia Less frequent -- -- Hyperuricaemia Less frequent -- -- Hypokalaemia Frequent -- -- Hyponatraemia Less frequent -- -- Psychiatric disorders Depression -- Less frequent -- Anxiety Less frequent -- -- Insomnia/sleep disturbances -- Less frequent -- Mood swings -- Less frequent -- Confusion -- Less frequent -- Nervous system disorders Coordination abnormal Less frequent -- -- Dizziness Less frequent Frequent -- Dizziness postural Less frequent -- -- Dysgeusia -- Less frequent -- Extrapyramidal syndrome -- Not known -- Headache Frequent Frequent -- Hypertonia -- Less frequent -- Paraesthesia Less frequent Less frequent -- Peripheral neuropathy, neuropathy -- Less frequent -- Somnolence Less frequent frequent -- Syncope -- Less frequent -- Tremor -- Less frequent -- Hypoesthesia -- Less frequent -- Eye disorders Visual disturbance Less frequent Less frequent -- Visual impairment Less frequent Less frequent -- Ear and labyrinth disorders Tinnitus Less frequent Less frequent -- Vertigo Less frequent -- Less frequent Cardiac disorders Palpitations Less frequent Frequent -- Syncope Less frequent -- -- Tachycardia Less frequent -- -- Dysrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation) -- Less frequent -- Myocardial infarction -- Less frequent -- Vascular disorders Flushing -- Frequent -- Hypotension Less frequent Less frequent -- Orthostatic hypotension Less frequent -- -- Vasculitis -- Less frequent Not known Respiratory, thoracic and mediastinal disorders Cough Less frequent Less frequent Less frequent Dyspnoea -- Less frequent -- Pharyngolaryngeal pain Less frequent -- -- Rhinitis -- Less frequent -- Abdominal discomfort, Less frequent Frequent Less frequent abdominal pain upper Gastro-intestinal disorders Change of bowel habit -- Less frequent -- Constipation Less frequent Less frequent -- Diarrhoea Less frequent Less frequent -- Dry mouth Less frequent Less frequent -- Dyspepsia -- Less frequent -- Gastritis -- Less frequent -- Gingival hyperplasia -- Less frequent -- Nausea Less frequent Frequent -- Pancreatitis -- Less frequent -- Vomiting -- Less frequent -- Liver function test abnormal, including blood bilirubin increase -- Less frequent* Not known Hepato-biliary disorders Hepatitis -- Less frequent -- Intrahepatic cholestasis, jaundice -- Less frequent -- Skin and subcutaneous tissue disorders Alopecia -- Less frequent -- Angioedema -- Less frequent Not known Dermatitis bullous -- -- Not known Erythema Less frequent -- -- Erythema multiforme -- Less frequent -- Exanthema Less frequent Less frequent -- Hyperhidrosis Less frequent Less frequent -- Photosensitivity reaction -- Less frequent -- Pruritus Less frequent Less frequent Not known Purpura -- Less frequent -- Rash Less frequent Less frequent Not known Skin discolouration Less frequent -- -- Urticaria and other forms of rash -- Less frequent -- Exfoliative dermatitis -- Less frequent -- Stevens-Johnson syndrome -- Less frequent -- Quincke oedema -- Less frequent -- Toxic Epidermal Necrolysis -- Not known -- Arthralgia Less frequent Less frequent -- Musculo-skeletal and connective tissue disorders Back pain Less frequent Less frequent -- Joint swelling Less frequent -- -- Muscle spasm Less frequent Less frequent -- Myalgia -- Less frequent Not known Ankle swelling -- Frequent -- Sensation of heaviness Less frequent -- -- Increased blood creatinine -- -- Not known Renal and urinary disorders Micturition disorder -- Less frequent -- Nocturia -- Less frequent -- Pollakiuria Less frequent Less frequent -- Polyuria Less frequent -- -- Renal failure and impairment -- -- Not known Impotence -- Less frequent -- Reproductive system and breast disorders Erectile dysfunction Less frequent -- -- Gynaecomastia -- Less frequent -- General disorders and administration site conditions Asthenia Frequent Less frequent -- Discomfort, malaise -- Less frequent -- Fatigue Frequent Frequent Less frequent Facial oedema Frequent -- -- Flushing, hot flush Frequent -- -- Non cardiac chest pain -- Less frequent -- Oedema Frequent Frequent -- Oedema peripheral Frequent -- -- Pain -- Less frequent -- Pitting oedema Frequent -- -- Increased serum potassium -- -- Not known Investigations Increased weight -- Less frequent -- Decreased weight -- Less frequent -- * Mostly consistent with cholestasis

Symptoms
The major symptom of overdose with valsartan is possibly pronounced hypotension with dizziness. Available data for amlodipine suggest that gross overdosage could result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported. Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24 u2013 48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Treatment
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 VALVASC 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.