4.1. Therapeutic indications

VIMOVO is indicated in adults for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, in patients who are at risk for developing non-steroidal anti-inflammatory drug (NSAID)-associated gastric and/or duodenal ulcers and where treatment with lower doses of naproxen or of other NSAIDs is not considered sufficient.

4.2. Posology and method of administration

Posology

The recommended dose is 1 tablet (500 mg/20 mg) twice daily.

Undesirable effects of naproxen may be minimised by using the lowest effective dose for the shortest duration possible (see section 4.4). In patients not treated with a NSAID previously, a lower daily dose of naproxen or of another NSAID should be considered. For this purpose non-fixed combination products are available. When total daily dose of 1000 mg of naproxen (500 mg twice daily) is not considered appropriate, alternative treatment with lower strength of naproxen or of other NSAIDs as non-fixed combination should be utilised.

Treatment should be continued to achieve individual treatment goals, reviewed at regular intervals and discontinued if no benefit or if worsening is seen.

Due to the delayed release of naproxen from the enteric-coated formulation (3-5 hours), VIMOVO is not intended for rapid relief of acute pain conditions (such as dental pain). However, flares of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis may be treated with VIMOVO.

Special populations

Renal impairment

In patients with mild to moderate renal impairment VIMOVO should be used cautiously and renal function should be monitored closely. A reduction in the total daily naproxen dose should be considered (see sections 4.4 and 4.5). When total daily dose of 1000 mg of naproxen (500 mg twice daily) is not considered appropriate, alternative treatment with lower strength of naproxen or of other NSAIDs as non-fixed combination should be utilised, and in addition the need for continuation of the gastroprotective treatment should be re-evaluated.

VIMOVO is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/minute) because accumulation of naproxen metabolites has been seen in patients with severe renal failure and in those on dialysis (see sections 4.3 and 4.4).

Hepatic impairment

In patients with mild to moderate hepatic impairment VIMOVO should be used cautiously and hepatic function should be monitored closely. A reduction in the total daily naproxen dose should be considered (see sections 4.4 and 5.2). When total daily dose of 1000 mg of naproxen (500 mg twice daily) is not considered appropriate, alternative treatment with lower strength of naproxen or of other NSAIDs as non-fixed combination should be utilised, and in addition the need for continuation of the gastroprotective treatment should be re-evaluated.

VIMOVO is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2).

Elderly (> 65 years)

Older people are at an increased risk of the serious consequences of adverse reactions (see sections 4.4 and 5.2). When total daily dose of 1000 mg of naproxen (500 mg twice daily) is not considered appropriate (e.g. in older people with impaired renal function or low body weight), alternative treatment with lower strength of naproxen or of other NSAIDs as non-fixed combination should be utilised, and in addition the need for continuation of the gastroprotective treatment should be re-evaluated.

Paediatric population

The safety and efficacy of VIMOVO in children aged 0 to 18 years has not been established. No data are available.

Method of administration

VIMOVO must be swallowed whole with water, and not split, chewed or crushed.

It is recommended that VIMOVO is taken at least 30 minutes prior to food intake (see section 5.2).

4.3. Contraindications

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or substituted benzimidazoles.

• History of asthma, urticaria or allergic-type reactions induced by administration of acetylsalicylic acid or other NSAIDs (see section 4.4).

• Third trimester of pregnancy (see section 4.6).

• Severe hepatic impairment (e.g. Child-Pugh C).

• Severe heart failure.

• Severe renal impairment.

• Active peptic ulceration (see section 4.4, gastrointestinal effects Naproxen).

• Gastrointestinal bleeding, cerebrovascular bleeding or other bleeding disorders (see section 4.4, Haematological effects).

• VIMOVO must not be used concomitantly with atazanavir and nelfinavir (see sections 4.4 and 4.5).

4.4. Special warnings and precautions for use

General

The combination of VIMOVO and NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided because of the cumulative risks of inducing serious NSAID‑related adverse events. VIMOVO can be used with low dose acetylsalicylic acid (see also section 4.5.).

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

To prevent overtreatment, the prescriber should assess at clinically meaningful intervals based on the individual risks and depending on the characteristics and the severity of the treated underlying disease, whether sufficient pain control is possible with lower doses of NSAIDs as non-fixed combinations.

When total daily dose of 1000 mg of naproxen (500 mg twice daily) is not considered appropriate, alternative treatment with lower strength of naproxen or of other NSAIDs as non‑fixed combination should be utilised, and in addition the need for continuation of the gastro protective treatment should be re-evaluated.

Risk-factors to develop NSAID related gastro-intestinal complications include high age, concomitant use of anticoagulants, corticosteroids, other NSAIDs including low-dose acetylsalicylic acid, debilitating cardiovascular disease, Helicobacter pylori infection, and a history of gastric and/or duodenal ulcers and upper gastrointestinal bleeding.

In patients with the following conditions, naproxen should only be used after a rigorous benefit-risk ratio:

• Inducible porphyries

• Systemic lupus erythematosus and mixed connective tissue disease, as rare cases of aseptic meningitis have been described in these patients.

Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.

VIMOVO contains very low levels of methyl- and propyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed). (See sections 2 and 6.1).

Elderly

Naproxen: Older people have an increased frequency of adverse reactions especially gastro-intestinal bleeding, and perforation, which may be fatal (see sections 4.2 and 5.2). The esomeprazole component of VIMOVO decreased the incidence of ulcers in older people.

Gastrointestinal effects

Naproxen: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation with NSAIDs is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in older people. These patients should begin treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose acetylsalicylic acid, or other drugs likely to increase gastrointestinal risk (see below and 4.5). The esomeprazole component of VIMOVO is a proton pump inhibitor.

Patients with a history of GI toxicity, particularly older people, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving NSAIDs with concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid (for information on use of VIMOVO with low-dose acetylsalicylic acid, see section 4.5).

Ulcer complications such as bleeding, perforation and obstruction were not studied in the VIMOVO trials.

When GI bleeding or ulceration occurs in patients receiving VIMOVO, the treatment should be withdrawn (see section 4.3).

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8 Undesirable effects).

Esomeprazole: In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with esomeprazole magnesium may alleviate symptoms and delay diagnosis.

Dyspepsia could still occur despite the addition of esomeprazole to the combination tablet (see section 5.1).

Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).

Esomeprazole, as all acid-blocking medicines, might reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors of reduced vitamin B12 absorption on long-term therapy.

Cardiovascular and cerebrovascular effects

Naproxen: Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). Although data suggest that the use of naproxen (1000 mg daily) may be associated with a lower risk, some risk cannot be excluded.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with naproxen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Renal effects Naproxen: Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics, angiotensin converting enzyme (ACE) inhibitors, or angiotensin II receptor antagonists and older people. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state (see also below, and sections 4.2 and 4.5).

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking esomeprazole and naproxen containing products and may occur at any point during Vimovo therapy (see section 4.8). Acute tubulointerstitial nephritis can progress to renal failure.

Vimovo should be discontinued in case of suspected TIN, and appropriate treatment should be promptly initiated.

Use in patients with renal impairmentAs naproxen and its metabolites are eliminated to a large extent (95%) by urinary excretion via glomerular filtration, it should be used with great caution in patients with impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients. VIMOVO is contraindicated in patients having a baseline creatinine clearance of less than 30 ml/minute (see section 4.3).

Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding.

Certain patients, specifically those whose renal blood flow is compromised, because of extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure, and pre-existing renal disease, should have renal function assessed before and during VIMOVO therapy. Some older patients in whom impaired renal function may be expected, as well as patients using diuretics, ACE‑inhibitors or angiotensin II receptor antagonists also fall within this category. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of naproxen metabolites in these patients.

Hepatic effects

Borderline elevations of one or more liver tests may occur in patients taking NSAIDs. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

Hepatorenal syndrome

The use of NSAIDs may be associated with acute renal failure in patients with severe hepato-cirrhosis. These patients frequently also have concomitant coagulopathy related to inadequate synthesis of clotting factors. Antiplatelet effects associated with naproxen could further increase risk of severe bleeding in these patients.

Haematological effects Naproxen: Patients who have coagulation disorders or are receiving drug therapy that interferes with haemostasis should be carefully observed if naproxen-containing products are administered.

Patients at high risk of bleeding and those on full anti-coagulation therapy (e.g. dicoumarol derivates) may be at increased risk of bleeding if given naproxen-containing products concurrently (see section 4.5).

Naproxen decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined.

When active and clinically significant bleeding from any source occurs in patients receiving VIMOVO, the treatment should be withdrawn.

Eye effects

Naproxen: Because of adverse eye findings in animal studies with NSAIDs, it is recommended that an ophthalmic examination be carried out if any change or disturbance in vision occurs.

Dermatological effects Naproxen: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring within the first month of treatment in the majority of cases. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in patients taking NSAIDs. VIMOVO should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Severe cutaneous adverse reactions (SCARs)

Esomeprazole: Severe cutaneous adverse reactions (SCARs) such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) which can be life-threatening or fatal, have been reported very rarely in association with esomeprazole treatment.

Patients should be advised of the signs and symptoms of the severe skin reaction EM/SJS/TEN/DRESS and should seek medical advice from their physician immediately when observing any indicative signs or symptoms. Vimovo should be discontinued immediately upon signs and symptoms of severe skin reactions and additional medical care/close monitoring should be provided as needed. Re-challenge should not be undertaken in patients with EM/SJS/TEN/DRESS.

Esomeprazole: Proton pump inhibitors are associated with very infrequent cases of subacute cutaneous lupus erythematosus (SCLE). If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping VIMOVO. SCLE after previous treatment with a proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.

Anaphylactic (anaphylactoid) reactions Naproxen: Hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions may occur both in patients with and without a history of hypersensitivity or exposure to acetylsalicylic acid, other NSAIDs or naproxen-containing products. They may also occur in individuals with a history of angio-oedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps.

Pre-existing asthma Naproxen: The use of acetylsalicylic acid in patients with acetylsalicylic acid-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between acetylsalicylic acid and other NSAIDs has been reported in such acetylsalicylic acid-sensitive patients, VIMOVO should not be administered to patients with this form of acetylsalicylic acid sensitivity (see section 4.3) and should be used with caution in patients with pre-existing asthma.

Inflammation Naproxen: The anti-pyretic and anti-inflammatory activities of naproxen may reduce fever and other signs of inflammation, thereby diminishing their utility as diagnostic signs.

Female fertility

The use of VIMOVO, as with any drug known to inhibit cyclooxygenase / prostaglandin synthesis, may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of VIMOVO should be considered (see section 4.6).

Combination with other medicinal products:

Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g. virus loading) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; esomeprazole 20 mg should not be exceeded and therefore VIMOVO must not be used concomitantly with atazanavir (see section 4.3).

Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with esomeprazole, the potential for interactions with drugs metabolised through CYP2C19 should be considered. An interaction is observed between clopidogrel and esomeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged.

Hypomagnesaemia

Severe hypomagnesaemia has been reported in patients treated with proton pump inhibitors (PPIs) like esomeprazole for at least three months, and in most cases for a year. Serious manifestations of hypomagnesaemia such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with digoxin or drugs that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Bone fracture

Proton pump inhibitors, especially if used in high doses and over long durations (> 1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in older people or in presence of other recognised risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10‑40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.

Interference with laboratory tests

Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, VIMOVO treatment should be stopped for at least 5 days before CgA measurements (see section 5.1). If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of proton pump inhibitor treatment.

VIMOVO 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

Contraindications of concomitant use (see section 4.3)

Antiretroviral agents

Omeprazole, the racemate of D+S omeprazole (esomeprazole), has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin). Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. Co-administration of omeprazole (40 mg qd) reduced mean nelfinavir AUC, Cmax and Cmin by 36–39% and mean AUC, Cmax and Cmin for the pharmacologically active metabolite M8 was reduced by 75-92%.

For other antiretroviral drugs, such as saquinavir, increased serum levels have been reported. There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole.

No interaction study has been performed with VIMOVO and atazanavir. However, due to the similar pharmacodynamic and pharmacokinetic properties of omeprazole and esomeprazole, the concomitant use of atazanavir and nelfinavir with esomeprazole is not recommended and concomitant administration with VIMOVO is contraindicated (see section 4.3).

Concomitant use with precaution

Other analgesics including cyclooxygenase-2 selective inhibitors

Concomitant use of two or more NSAIDs should be avoided as this may increase the risk of adverse effects, especially gastrointestinal ulcers and bleeding. The concomitant use of VIMOVO with other NSAIDs, except for low-dose acetylsalicylic acid (≤ 325 mg/day), is not recommended (see section 4.4).

Acetylsalicylic acid

VIMOVO can be administered with low-dose acetylsalicylic acid (≤325 mg/day) therapy. In clinical trials, patients taking VIMOVO in combination with low-dose acetylsalicylic acid did not have an increased occurrence of gastric ulcers compared to patients taking VIMOVO alone (see section 5.1). However, the concurrent use of acetylsalicylic acid and VIMOVO may still increase the risk of serious adverse events (see sections 4.4 and 4.8).

Clinical pharmacodynamic data suggest that concomitant naproxen usage for more than one day consecutively may inhibit the effect of low-dose acetylsalicylic acid on platelet activity and this inhibition may persist for up to several days after stopping naproxen therapy. The clinical relevance of this interaction is not known.

Tacrolimus

As with all NSAIDs, there is a possible risk of nephrotoxicity when naproxen is co-administered with tacrolimus. Concomitant administration of esomeprazole has been reported to increase the serum levels of tacrolimus. During treatment with VIMOVO, a reinforced monitoring of tacrolimus concentrations as well as renal function (creatinine clearance) should be performed, and dosage of tacrolimus adjusted if needed.

Ciclosporin

As with all NSAIDs, caution is advised when ciclosporin is co-administered because of the increased risk of nephrotoxicity.

Diuretics

Clinical studies, as well as postmarketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy (see section 4.4).

Selective Serotonin Reuptake Inhibitors (SSRIs)

Concomitant use of NSAIDs, including COX-2 selective inhibitors, and SSRIs increases the risk of gastrointestinal bleeding (see section 4.4).

Corticosteroids

There is an increased risk of gastrointestinal bleeding when corticosteroids are combined with NSAIDs including COX–2 selective inhibitors. Caution should be used when NSAIDs are administered concomitantly with corticosteroids (see section 4.4).

ACE-inhibitors/Angiotensin II receptor antagonists

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II receptor antagonists. NSAIDs may also increase the risk of renal impairment associated with the use of ACE-inhibitors or angiotensin II receptor antagonists. The combination of NSAIDs and ACE-inhibitors or angiotensin II receptor antagonists should be given with caution in patients who are older, volume-depleted, or with impaired renal function (see section 4.4).

Digoxin

NSAIDs may increase plasma cardiac glycoside levels when co-administered with cardiac glycosides such as digoxin.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate

When given together with proton pump inhibitors, methotrexate levels have been reported to increase in some patients. NSAIDs have been reported to reduce the tubular secretion of methotrexate in an animal model. This may indicate that both esomeprazole and naproxen could enhance the toxicity of methotrexate. The clinical relevance is likely to be greater in patients receiving high doses of methotrexate and in patients with renal dysfunction. Caution should be used when VIMOVO is administered concomitantly with methotrexate. In high‑dose methotrexate administration a temporary withdrawal of VIMOVO is recommended.

Sulphonylureas, Hydantoins

Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as sulphonylureas, and hydantoins. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Clopidogrel

Results from studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg p.o. daily) resulting in decreased exposure to the active metabolite of clopidogrel by an average of 40%, and resulting in decreased maximum inhibition of (ADP induced) platelet aggregation by an average of 14%.

In a study in healthy subjects, there was a decreased exposure by almost 40% of the active metabolite of clopidogrel when a fixed dose combination of esomeprazole 20 mg and acetylsalicylic acid 81 mg was given with clopidogrel compared to clopidogrel alone. However, the maximum levels of inhibition of (ADP induced) platelet aggregation in these subjects were the same in both groups.

No clinical studies on the interaction between clopidogrel and the fixed dose combination of naproxen+esomeprazole (VIMOVO) have been performed.

Inconsistent data on the clinical implications of a PK/PD interaction of esomeprazole in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of VIMOVO and clopidogrel should be discouraged (see section 4.4).

Anti-coagulants and thrombocyte aggregation inhibitors

NSAIDs may enhance the effects of oral anti-coagulants (e.g. warfarin, dicoumarol) heparins and thrombocyte aggregation inhibitors (see section 4.4).

Concomitant administration of 40 mg esomeprazole to warfarin-treated patients showed that, despite a slight elevation in the trough plasma concentration of the less potent R isomer of warfarin, the coagulation times were within the accepted range. However, from post marketed use cases of elevated INR of clinical significance have been reported during concomitant treatment with warfarin. Close monitoring is recommended when initiating and ending treatment with warfarin or other coumarine derivatives.

Beta receptor-blockers

Naproxen and other NSAIDs can reduce the antihypertensive effect of propranolol and other beta-blockers.

Probenecid

Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.

Drugs with gastric pH-dependent absorption

The gastric acid suppression during treatment with esomeprazole and other PPIs might decrease or increase the absorption of drugs with a gastric pH dependent absorption. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, itraconazole, posaconazole and erlotinib can decrease while the absorption of drugs such as digoxin can increase during treatment with esomeprazole. Concomitant use with posaconazole and erlotinib should be avoided. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects).

Other Information Concerning Drug Interactions

Studies evaluating concomitant administration of esomeprazole and either naproxen (non-selective NSAID) or rofecoxib (COX-2-selective NSAID) did not identify any clinically relevant interaction.

As with other NSAIDs, concomitant administration of cholestyramine can delay the absorption of naproxen.

In healthy volunteers, concomitant administration of 40 mg esomeprazole resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t1/2) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole (see also section 4.4).

Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin and quinidine.

Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Esomeprazole is also metabolised by CYP3A4. The following have been observed in relation to these enzymes:

• Concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. This interaction is unlikely to be of clinical relevance.

• Concomitant administration of 40 mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients.

• Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure.

• Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg twice daily), resulted in a doubling of the exposure (AUC) to esomeprazole.

Dose adjustment of esomeprazole is not required in any of these cases.

Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's Wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.

Omeprazole as well as esomeprazole act as inhibitors of CYP 2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.

Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking quinolones may have an increased risk of developing convulsions.

Drug/Laboratory Test Interaction

Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined.

The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.

Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).

4.6. Fertility, pregnancy and lactation

Pregnancy

Naproxen:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period (see section 5.3).

In women attempting to conceive or during the first and second trimester of pregnancy, VIMOVO should not be given unless the potential benefit to the patient outweighs the potential risk to the foetus.

From the 20th week of pregnancy onward, VIMOVO use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, if naproxen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and the duration of treatment as short as possible.

Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to VIMOVO for several days from gestational week 20 onward. VIMOVO should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (premature constriction / closure of the ductus arteriosus and pulmonary hypertension);

• renal dysfunction (see above);

the mother and the neonate, at the end of pregnancy, to:

• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses.

• inhibition of uterine contractions resulting in delayed or prolonged labour.

Consequently, VIMOVO is contraindicated during the third trimester of pregnancy (see section 4.3).

Esomeprazole:

There are limited amount of data from the use of esomeprazole in pregnant women. With the racemic mixture omeprazole, data on a larger number of exposed pregnancies stemming from epidemiological studies indicate no malformative nor foetotoxic effects. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/foetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development.

Breast-feeding

Naproxen is excreted in low quantities in human milk. It is unknown whether esomeprazole is excreted in human milk. A published case report on the racemic mixture omeprazole indicated excretion of low quantities in the human breast milk (weight adjusted dose < 7%). VIMOVO should not be used during breastfeeding.

Fertility

The use of NSAIDs like naproxen may impair female fertility. The use of VIMOVO is not recommended in women attempting to conceive (see section 4.4).

4.7. Effects on ability to drive and use machines

VIMOVO has minor influence on the ability to drive and use machines; based on that some of the adverse effects (e.g. dizziness) reported following the use of VIMOVO may reduce the ability to react.

4.8. Undesirable effects

Summary of safety profile

Immediate release esomeprazole has been included in the tablet formulation to decrease the incidence of gastrointestinal side effects from naproxen. VIMOVO has been shown to significantly decrease the occurrence of gastric ulcers and NSAID associated upper gastrointestinal adverse events compared to naproxen alone (see section 5.1).

No new safety findings were identified during VIMOVO treatment in the overall study population (n=1157) compared to the well-established safety profiles of the individual active substances naproxen and esomeprazole.

Tabulated summary of adverse reactions

Adverse reactions are classified according to frequency and System Organ Class. Frequency categories are defined according to 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).

VIMOVO

The following adverse experiences have been reported in patients taking VIMOVO during clinical trials:

Very Common

Common

Uncommon

Rare

Infections and infestations

infection

diverticulitis

Blood and lymphatic system disorders

eosinophilia, leucopenia

Immune system disorders

hypersensitivity reactions

Metabolism and nutrition disorders

appetite disorder

fluid retention, hyperkalemia, hyperuricemia

Psychiatric disorders

anxiety, depression, insomnia

confusion, dream abnormalities

Nervous system disorders

dizziness, headache, taste disturbance

paraesthesia, syncope

somnolence, tremor

Ear and labyrinth disorders

tinnitus, vertigo

Cardiac disorders

arrhythmia, palpitations

myocardial infarction, tachycardia

Vascular disorders

hypertension

Respiratory, thoracic and mediastinal disorders

asthma, bronchospasm, dyspnea

Gastrointestinal disorders

dyspepsia

abdominal pain, constipation, diarrhoea, esophagitis, flatulence, gastric/duodenal ulcers*, gastritis, nausea, vomiting

dry mouth, eructation, gastrointestinal bleeding, stomatitis

glossitis, hematemesis, rectal bleeding

Skin and subcutaneous tissue disorders

skin rashes

dermatitis, hyperhidrosis, pruritus, urticaria

alopecia, ecchymoses

Musculoskeletal and connective tissue disorders

arthralgia

myalgia

Renal and urinary disorders

proteinuria, renal failure

Reproductive system and breast disorders

menstrual disorder

General disorders and administration site disorders

oedema

asthenia, fatigue, pyrexia

Investigations

abnormal liver function tests, raised serum creatinine

*as detected by scheduled routine endoscopy

Naproxen

The following adverse experiences have been reported in patients taking naproxen during clinical trials and through postmarketing reports.

Common

Uncommon/Rare

Infections and infestations

diverticulitis

aseptic meningitis, infection, sepsis

Blood and lymphatic system disorders

agranulocytosis, aplastic anemia, eosinophilia, granulocytopenia, hemolytic anemia, leucopenia, lymphadenopathy, pancytopenia, thrombocytopenia

Immune system disorders

anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions

Metabolism and nutrition disorders

appetite disorder, fluid retention, hyperglycemia, hyperkalemia, hyperuricemia, hypoglycemia, weight changes

Psychiatric disorders

depression, insomnia

agitation, anxiety, confusion, dream abnormalities, hallucinations, nervousness

Nervous system disorders

dizziness, drowsiness, headache, lightheadedness, vertigo

cognitive dysfunction, coma, convulsions, inability to concentrate, optic neuritis, paresthesia, syncope, tremor

Eye disorders

visual disturbances

blurred vision, conjunctivitis, corneal opacity, papilloedema, papillitis

Ear and labyrinth disorders

tinnitus, hearing disturbances

hearing impairment

Cardiac disorders

palpitations

arrhythmia, congestive heart failure, myocardial infarction, tachycardia

Vascular disorders

hypertension, hypotension, vasculitis

Respiratory, thoracic and mediastinal disorders

dyspnea

asthma, bronchospasm, eosinophilic pneumonitis, pneumonia, pulmonary edema, respiratory depression

Gastrointestinal disorders

dyspepsia, abdominal pain, nausea, vomiting, diarrhoea, constipation, heartburn, peptic ulcers, stomatitis

dry mouth, esophagitis, gastric ulcers, gastritis, glossitis, eructation, flatulence, gastric/duodenal ulcers, gastrointestinal bleeding and/or perforation, melena, hematemesis, pancreatitis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease), nonpeptic gastrointestinal ulceration, rectal bleeding, ulcerative stomatitis

Hepatobiliary disorders

cholestasis, hepatitis, jaundice, liver failure

Skin and subcutaneous tissue disorders

pruritus, ecchymoses, purpura, skin rashes

alopecia, exanthema,urticaria, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN), erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, systemic lupus erythematosus, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria), exfoliative dermatitis, angioneurotic edema, pustular reaction

Musculoskeletal and connective tissue disorders

muscle weakness, myalgia

Renal and urinary disorders

glomerular nephritis, hematuria, tubulointerstitial nephritis (with possible progression to renal failure), nephrotic syndrome, oliguria/polyuria, proteinuria, renal failure, renal papillary necrosis, tubular necrosis

Reproductive system and breast disorders

infertility, menstrual disorder

General disorders and administration site disorders

fatigue, oedema, sweating, thirst

asthenia, malaise, pyrexia

Investigations

abnormal liver function tests, increased bleeding time, raised serum creatinine

Esomeprazole:

The following adverse drug reactions have been identified or suspected in the clinical trials programme for enteric-coated esomeprazole and/or from post marketing use. None were found to be dose-related.

Common

Uncommon

Rare

Very rare

Not known

Blood and lymphatic system disorders

leukopenia, thrombocytopenia

agranulocytosis, pancytopenia

Immune system disorders

hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock

Metabolism and nutrition disorders

peripheral oedema

hyponatraemia

hypomagnesaemia, severe hypomagnesaemia may result in hypocalcaemia; hypomagnesaemia may also be associated with hypokalaemia.

Psychiatric disorders

insomnia

agitation, confusion, depression

aggression, hallucinations

Nervous system disorders

headache

dizziness, paraesthesia, somnolence

taste disturbance

Eye disorders

blurred vision

Ear and labyrinth disorders

vertigo

Respiratory, thoracic and mediastinal disorders

bronchospasm

Gastrointestinal disorders

abdominal pain, diarrhoea, flatulence, nausea/vomiting, constipation, fundic gland polyps (benign)

dry mouth

stomatitis, gastrointestinal candidiasis

microscopic colitis

Hepatobiliary disorders

increased liver enzymes

hepatitis with or without jaundice

hepatic failure, hepatic encephalopathy in patients with pre-existing liver disease

Skin and subcutaneous tissue disorders

dermatitis, pruritus, urticaria, rash

alopecia, photosensitivity

erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS)

Subacute cutaneous lupus erythematos-us (see section 4.4)

Musculoskeletal and connective tissue disorders

fracture of the hip, wrist or spine (see section 4.4)

arthralgia, myalgia

muscular weakness

Renal and urinary disorders

Tubulointerstitial nephritis (with possible progression to renal failure)

Reproductive system and breast disorders

gynaecomastia

General disorders and administration site disorders

malaise, increased sweating

Description of selected adverse reactions

Naproxen

Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although data suggest that the use of naproxen (1000 mg daily) may be associated with a lower risk, some risk cannot be excluded (see section 4.4).

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in older people, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4 - Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis has been observed.

VIMOVO has been developed with esomeprazole to decrease the incidence of gastrointestinal side effects from naproxen and has been shown to significantly decrease the occurrence of gastric and/or duodenal ulcers and NSAID associated upper gastrointestinal adverse events compared to naproxen alone.

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There is no clinical data on overdose with VIMOVO.

Any effects of an overdose with VIMOVO would be expected to primarily reflect the effects of an overdose with naproxen.

Symptoms

Related to naproxen overdose

Significant naproxen overdosage may be characterized by lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting.

Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life-threatening.

Related to esomeprazole overdose

The symptoms described in connection with deliberate esomeprazole overdose (limited experience of doses in excess of 240 mg/day) are transient. Single doses of 80 mg esomeprazole were uneventful.

Management

Related to naproxen

Patients should be managed by symptomatic and supportive care following a NSAID overdose, particularly with respect to GI effects and renal damage. There are no specific antidotes.

Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may not be useful due to high protein binding.

Related to esomeprazole

No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.