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
Patients with 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-eva luated.
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).
Patients with 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-eva luated.
VIMOVO is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2).
Older people (>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-eva luated.
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).
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-eva luated.
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 erythematosis 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).
Older people
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.
Dyspesia could still occur despite the addition of esomperazole 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).
Use in patients with impaired renal function
As 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. VIMOVO should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
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.
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).
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
