Gemvalaz, Valgamez 160 mg Film-Coated Tablets

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

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

Posology

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

Special populations

In Elderly: Normal dosage regimens are recommended.

Children and adolescents: GEMVALAZ 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 GEMVALAZ to patients with hepatic impairment or biliary obstructive disorders (see sections 4.4 and 4.8).

Method of administration

For oral use. It is recommended to take GEMVALAZ with some water.

• Hypersensitivity to amlodipine, valsartan, or to dihydropyridine derivatives, or to any of the inactive ingredients of GEMVALAZ 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.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance less than 30 ml/min).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis.
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride. (see section 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.
• Porphyria.
• Lithium therapy: Concomitant administration with GEMVALAZ may lead to toxic blood concentrations of lithium. (see section 4.5).
• The concomitant use of GEMVALAZ with aliskiren-containing products is contraindicated. (see sections 4.4 and 4.5).
• Severe hepatic impairment, biliary cirrhosis or cholestasis.
• Severe hypotension.
• Shock (including cardiogenic shock).
• Haemodynamically unstable heart failure after acute myocardial infarction.
• Pregnancy and lactation. (Section 4.6).

Should a woman become pregnant while receiving GEMVALAZ, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see section 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). Dual blockade of RAAS through the combined use of GEMVALAZ and aliskiren is therefore contraindicated (see section 4.3).

GEMVALAZ should not be used concomitantly with aliskiren. (see section 4.3).

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 GEMVALAZ or close medical supervision at the start of treatment is recommended.

If hypotension occurs with GEMVALAZ, 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 medicines that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels (see Section 4.3 and 4.5).

Renal artery stenosis

GEMVALAZ should be used with caution to treat hypertension in patients with unilateral renal artery stenosis since blood urea and serum creatinine may increase in such patients.

Kidney transplantation

To date there is no experience of the safe use of GEMVALAZ in patients who have had 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 GEMVALAZ 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.

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. GEMVALAZ should be discontinued immediately in patients who develop angioedema and should not be re-administered.

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 ureamia 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.

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.

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).

To be taken into account with concomitant use

Other antihypertensive medicines commonly used antihypertensive medicines (e.g. alpha blockers, diuretics) and other medicines 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 medicines [e.g. carbamazepine, phenobarbitone, 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 amlodipine/valsartan.

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels: If a medicine 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 has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (see sections 4.3 and 4.4).

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

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

Women of childbearing potential / Contraception in males and females: Women of childbearing age should ensure effective contraception.

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

Breastfeeding: GEMVALAZ is contraindicated during lactation. 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. GEMVALAZ.

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

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 -- Less frequent -- tachycardia, and atrial fibrillation) 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 -- Gastro - intestinal disorders Abdominal discomfort, abdominal pain upper Less frequent Frequent Less frequent 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 -- Hepato - biliary disorders Liver function test abnormal, including blood bilirubin increase part of below -- Less frequent* Not known Hepatitis -- Less frequent -- Intrahepatic cholestasis, -- 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 -- Musculo - skeletal and connective tissue disorders Arthralgia Less frequent Less frequent -- 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 -- Repro - ductive 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 part of investigations -- -- Not known Investigations Increased weight -- Less frequent -- Decreased weight -- Less frequent -- * Mostly consistent with cholestasis

Symptoms

There is no experience of overdose with GEMVALAZ. 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. 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 ventilator support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Treatment

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 GEMVALAZ 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.