1. Name Of The Medicinal Product
VIMOVO™ 500 mg/20 mg modified-release tablets
2. Qualitative And Quantitative Composition
Each modified-release tablet contains 500 mg naproxen and 20 mg esomeprazole (as magnesium trihydrate).
VIMOVO contains very low, non-preserving levels of 0.02 mg methyl parahydroxybenzoate and 0.01 mg propyl parahydroxybenzoate (see sections 4.4 and 6.1).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Modified-release tablet containing enteric-coated (gastro-resistant) naproxen and film-coated esomeprazole.
Oval, biconvex, yellow tablet marked '500/20' in black ink.
4. Clinical Particulars
4.1 Therapeutic Indications
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 in adults
The 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. When total daily dose of 1000 mg of naproxen is not considered appropriate, alternative therapeutic regimens should be utilized.
Treatment should be continued to achieve individual treatment goals, reviewed at regular intervals and discontinued if no benefit seen.
Due to the delayed release of naproxen from the enteric-coated formulation, VIMOVO is not intended for the treatment of acute pain conditions (such as dental pain or gout). However, flares of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis may be treated with VIMOVO.
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).
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 is considered not appropriate, alternative therapeutic regimens should be utilized.
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 is considered not appropriate, alternative therapeutic regimens should be utilized.
VIMOVO is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2).
Elderly (>65 years)
The elderly 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 is considered not appropriate (e.g. in elderly with impaired renal function or low body weight), alternative therapeutic regimens should be utilized.
Children (
VIMOVO is not recommended for use in children, due to lack of data on safety and efficacy.
4.3 Contraindications
• Known hypersensitivity to naproxen, esomeprazole, substituted benzimidazoles, or to any of the excipients
• History of asthma, urticaria or allergic-type reactions induced by administration of aspirin or other NSAIDs (see section 4.4)
• Third trimester of pregnancy (see section 4.6)
• Severe hepatic impairment (e.g. Childs-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 use of VIMOVO with other concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided. VIMOVO can be used with low dose aspirin. (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).
When total daily dose of 1000 mg of naproxen is considered not appropriate, alternative therapeutic regimens should be utilized.
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, and a history of gastric and/or duodenal ulcers.
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. There may be an increased risk of aseptic meningitis 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: The elderly 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 elderly.
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 the elderly. 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 aspirin, 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 when elderly, 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 aspirin (for information on use of VIMOVO with low-dose aspirin, 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 and ACE inhibitors, and the elderly. 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 is 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 elderly patients in whom impaired renal function may be expected, as well as patients using diuretics, may 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.
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 aspirin, 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 aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, VIMOVO should not be administered to patients with this form of aspirin 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 omeprazole (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of esomeprazole and clopidogrel should be discouraged.
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 aspirin (< 325 mg/day), is not recommended (see section 4.4).
Aspirin
VIMOVO can be administered with low-dose aspirin (
Ciclosporin and tacrolimus
As with other non-steroidal anti-inflammatory drugs, caution is advised when ciclosporin is co-administered because of the increased risk of nephrotoxicity.
There is a possible risk of nephrotoxicity when NSAIDs are given with tacrolimus.
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
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors, and may increase the risk of renal impairment associated with the use of ACE-inhibitors. Therefore, the combination should be given with caution in patients with impaired renal function, especially elderly patients.
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
Caution is advised where methotrexate is administered concurrently because of possible enhancement of its toxicity, since naproxen, in common with other non-steroidal anti-inflammatory drugs, has been reported to reduce the tubular secretion of methotrexate in an animal model.
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
In a crossover clinical study, clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when clopidogrel and omeprazole were administered together. In another study it was shown that administering clopidogrel and omeprazole at different times did not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19. Esomeprazole is expected to give a similar interaction with clopidogrel.
Inconsistent data on the clinical implications of this PK/PD interaction in terms of major cardiovascular events have been reported from both observational and clinical studies.
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 esomprazole 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 CYP2C19. 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 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.
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/fetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development.
During the first and second trimester of pregnancy, VIMOVO should not be given unless clearly necessary. If VIMOVO is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the duration of treatment should be kept as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:
• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;
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.
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).
Breastfeeding
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.
4.7 Effects On Ability To Drive And Use Machines
When driving vehicles or operating machines it should be taken into account 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
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Common
|
Uncommon
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Rare
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Infections and infestations
|
|
|
infection
|
diverticulitis
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Blood and lymphatic system disorders
|
|
|
|
eosinophilia, leucopenia
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Immune system disorders
|
|
|
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hypersensitivity reactions
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Metabolism and nutrition disorders
|
|
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appetite disorder
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fluid retention, hyperkalemia, hyperuricemia
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Psychiatric disorders
|
|
|
anxiety, depression, insomnia
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confusion, dream abnormalities
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Nervous system disorders
|
|
dizziness, headache, taste disturbance
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paraesthesia, syncope
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somnolence, tremor
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Ear and labyrinth disorders
|
|
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tinnitus, vertigo
|
|
Cardiac disorders
|
|
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arrhythmia, palpitations
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myocardial infarction, tachycardia
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Vascular disorders
|
|
hypertension
|
|
|
Respiratory, thoracic and mediastinal disorders
|
|
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asthma, bronchospasm, dyspnea
|
|
Gastrointestinal disorders
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dyspepsia
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abdominal pain, constipation, diarrhoea, esophagitis, flatulence, gastric/duodenal ulcers*, gastritis, nausea, vomiting
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dry mouth, eructation, gastrointestinal bleeding, stomatitis
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glossitis, hematemesis, rectal bleeding
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Skin and subcutaneous tissue disorders
|
|
skin rashes
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dermatitis, hyperhidrosis, pruritis, urticaria
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alopecia, ecchymoses
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Musculoskeletal and connective tissue disorders
|
|
arthralgia
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myalgia
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Renal and urinary disorders
|
|
|
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proteinuria, renal failure
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Reproductive system and breast disorders
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|
|
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menstrual disorder
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General disorders and administration site disorders
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oedema
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asthenia, fatigue, pyrexia
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Investigations
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|
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abnormal liver function tests, raised serum creatinine
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|
*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
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Uncommon/Rare
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Infections and infestations
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diverticulitis
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aseptic meningitis, infection, sepsis
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Blood and lymphatic system disorders
|
|
agranulocytosis, aplastic anemia, eosinophilia, granulocytopenia, hemolytic anemia, leucopenia, lymphadenopathy, pancytopenia, thrombocytopenia
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Immune system disorders
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anaphylactic reactions, anaphylactoid reactions, hypersensitivity reactions
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Metabolism and nutrition disorders
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appetite disorder, fluid retention, hyperglycemia, hyperkalemia, hyperuricemia, hypoglycemia, weight changes
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Psychiatric disorders
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depression, insomnia
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agitation, anxiety, confusion, dream abnormalities, hallucinations, nervousness
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Nervous system disorders
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dizziness, drowsiness, headache, lightheadedness, vertigo
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cognitive dysfunction, coma, convulsions, inability to concentrate, optic neuritis, paresthesia, syncope, tremor
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Eye disorders
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visual disturbances
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blurred vision, conjunctivitis, corneal opacity, papilloedema, papillitis
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Ear and labyrinth disorders
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tinnitus, hearing disturbances
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hearing impairment
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Cardiac disorders
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palpitations
|
arrhythmia, congestive heart failure, myocardial infarction, tachycardia
|
Vascular disorders
|
|
hypertension, hypotension, vasculitis
|
|
