Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
The safety and efficacy of amlodipine in hypertensive crisis have not been established.
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).
Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Exforge 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 Exforge or close medical supervision at the start of treatment is recommended.
If hypotension occurs with Exforge, 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.
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.
Exforge 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.
To date there is no experience of the safe use of Exforge in patients who have had a recent kidney transplantation.
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 Exforge 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.
No dosage adjustment of Exforge 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.
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, 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. Exforge should be discontinued immediately in patients who develop angioedema and should not be re-administered.
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.
As with all other vasodilators, special caution is indicated in patients suffering from mitral stenosis or significant aortic stenosis that is not high grade.
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.
Exforge has not been studied in any patient population other than hypertension.
No drug-drug interaction studies have been performed with Exforge and other medicinal products.
Commonly used antihypertensive agents (e.g. alpha blockers, diuretics) and other medicinal 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.
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.
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.
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).
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.
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.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or ciclosporin.
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. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use. If a diurectic is also used, the risk of lithium toxicity may presumably be increased further with Exforge.
If a medicinal product that affects potassium levels is to be prescribed in combination with valsartan, monitoring of potassium plasma levels is advised.
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.
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.
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).
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.
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.
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 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).
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. No information is available regarding the use of Exforge during breast-feeding, therefore Exforge is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
There are no clinical studies on fertility with Exforge.
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).
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).
Patients taking Exforge 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.
The safety of Exforge 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.
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 | ||
|---|---|---|---|---|
| Exforge | Amlodipine | Valsartan | ||
| Infections and infestations | Nasopharyngitis | Common | -- | -- |
| Influenza | Common | -- | -- | |
| Blood and lymphatic system disorders | Haemoglobin and 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 | Anorexia | Uncommon | -- | -- |
| Hypercalcaemia | Uncommon | -- | -- | |
| Hyperglycaemia | -- | Very rare | -- | |
| Hyperlipidaemia | Uncommon | -- | -- | |
| Hyperuricaemia | Uncommon | -- | -- | |
| Hypokalaemia | Common | -- | -- | |
| 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 syndrome | -- | 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 | -- | |
| 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
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.
Adverse reactions previously reported with one of the individual components (amlodipine or valsartan) may be potential adverse reactions with Exforge as well, even if not observed in clinical trials or during the post-marketing period.
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, StevensJohnson syndrome, Quincke oedema, photosensitivity.
Not known: Toxic Epidermal Necrolysis
* mostly consistent with cholestasis
Exceptional cases of extrapyramidal syndrome have been reported.
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 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 national reporting system listed in Appendix V.
Not applicable.
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