Indications:
VIVIDOL is a combination product that contains naproxen and esomeprazole. It is indicated for the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID associated gastric ulcers. VIVIDOL is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. Controlled studies do not extend beyond 6 months.
Dosage and administration:
Carefully consider the potential benefits and risks of VIVIDOL and other treatment options before deciding to use VIVIDOL. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. VIVIDOL does not allow for administration of a lower daily dose of esomeprazole. If a dose of esomeprazole lower than a total daily dose of 40 mg is more appropriate, a different treatment should be considered.
Rheumatoid arthritis, osteoarthritis and ankylosing spondylitis:
The dosage is one tablet twice daily of VIVIDOL 375 mg naproxen and 20 mg of esomeprazole or 500 mg naproxen and 20 mg of esomeprazole. The tablets are to be swallowed whole with liquid. Do not split, chew, crush or dissolve the tablet. VIVIDOL is to be taken at least 30 minutes before meals.
Geriatric patients:
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Use caution when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly use the lowest effective dose.
Patients with moderate to severe renal impairment:
Naproxen-containing products are not recommended for use in patients with moderate to severe or severe renal impairment (creatinine clearance < 30 ml/min).
Hepatic insufficiency:
Monitor patients with mild to moderate hepatic impairment closely and consider a possible dose reduction based on the naproxen component of VIVIDOL.
VIVIDOL is not recommended in patients with severe hepatic impairment because esomeprazole doses should not exceed 20 mg daily in these patients.
Pediatric patients:
The safety and efficacy of VIVIDOL in children younger than 18 years has not been established. VIVIDOL is therefore not recommended for use in children.
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling this medicine after use.
Contraindications:
VIVIDOL is contraindicated in patients with known hypersensitivity to naproxen, esomeprazole magnesium, substituted benzimidazoles, or to any of the excipients.
VIVIDOL is contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
Hypersensitivity reactions, eg, angioedema and anaphylactic reaction/shock, have been reported with esomeprazole use.
VIVIDOL is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.
VIVIDOL is contraindicated in patients in the late stages of pregnancy.
Special warnings and precautions for use:
General
The combination of VIVIDOL and NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided because of the cumulative risks of inducing serious NSAID-related adverse events. VIVIDOL 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.
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.
VIVIDOL contains very low levels of methyl- and propyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed).
Elderly
Naproxen: Older people have an increased frequency of adverse reactions especially gastro-intestinal bleeding, and perforation, which may be fatal. The esomeprazole component of VIVIDOL 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 , 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 VIVIDOL 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.
Ulcer complications such as bleeding, perforation and obstruction were not studied in the VIVIDOL trials.
When GI bleeding or ulceration occurs in patients receiving VIVIDOL, the treatment should be withdrawn.
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.
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.
Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.
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 renal impairment
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. VIVIDOL is contraindicated in patients having a baseline creatinine clearance of less than 30 ml/minute.
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 VIVIDOL 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.
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 VIVIDOL, 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. 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. VIVIDOL 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 VIVIDOL. 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, VIVIDOL should not be administered to patients with this form of acetylsalicylic acid sensitivity 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 VIVIDOL, 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 VIVIDOL should be considered.
Combination with other medicinal products:
Co-administration of atazanavir with proton pump inhibitors is not recommended. 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 VIVIDOL must not be used concomitantly with atazanavir.
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. 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, VIVIDOL treatment should be stopped for at least 5 days before CgA measurements. 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.
VIVIDOL contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
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.
In women attempting to conceive or during the first and second trimester of pregnancy, VIVIDOL should not be given unless the potential benefit to the patient outweighs the potential risk to the foetus. If VIVIDOL 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, VIVIDOL is contraindicated during the third trimester of pregnancy.
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%). VIVIDOL should not be used during breastfeeding.
Fertility
The use of NSAIDs like naproxen may impair female fertility. The use of VIVIDOL is not recommended in women attempting to conceive.
Effects on ability to drive and use machines:
VIVIDOL 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 VIVIDOL may reduce the ability to react.
Interaction with other medicinal products and other forms of interaction:
Contraindications of concomitant use
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 VIVIDOL 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 VIVIDOL is contraindicated.
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 VIVIDOL with other NSAIDs, except for low-dose acetylsalicylic acid (≤ 325 mg/day), is not recommended.
Acetylsalicylic acid
VIVIDOL can be administered with low-dose acetylsalicylic acid (≤ 325 mg/day) therapy. In clinical trials, patients taking VIVIDOL in combination with low-dose acetylsalicylic acid did not have an increased occurrence of gastric ulcers compared to patients taking VIVIDOL alone. However, the concurrent use of acetylsalicylic acid and VIVIDOL may still increase the risk of serious adverse events.
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 VIVIDOL, 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.
Selective Serotonin Reuptake Inhibitors (SSRIs)
Concomitant use of NSAIDs, including COX-2 selective inhibitors, and SSRIs increases the risk of gastrointestinal bleeding.
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.
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.
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 VIVIDOL is administered concomitantly with methotrexate. In high-dose methotrexate administration a temporary withdrawal of VIVIDOL 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 (VIVIDOL) 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 VIVIDOL and clopidogrel should be discouraged.
Anti-coagulants and thrombocyte aggregation inhibitors
NSAIDs may enhance the effects of oral anti-coagulants (e.g. warfarin, dicoumarol) heparins and thrombocyte aggregation inhibitors.
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).
Incompatibilities:
Because there are no studies of drug incompatibility, do not mix this drug with other drugs.
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. VIVIDOL has been shown to significantly decrease the occurrence of gastric ulcers and NSAID associated upper gastrointestinal adverse events compared to naproxen alone.
No new safety findings were identified during naproxen/esomeprasole 500 mg/20 mg 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).
Naproxen/esomeprasole 500 mg/20 mg
The following adverse experiences have been reported in patients taking naproxen/esomeprasole 500 mg/20 mg 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, interstitial nephritis, 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 | hypomagne-saemia, 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) | Subacute cutaneous lupus erythematos-us | |
| Musculoskeletal and connective tissue disorders | fracture of the hip, wrist or spine | arthralgia, myalgia | muscular weakness | ||
| Renal and urinary disorders | Interstitial nephritis | ||||
| 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.
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. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been observed.
VIVIDOL 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.
Overdose:
There is no clinical data on overdose with VIVIDOL.
Any effects of an overdose with VIVIDOL 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.
Pharmacodynamics:
Pharmacotherapeutic group: naproxen and esomeprazole
ATC code: M01AE52
Mechanism of action
VIVIDOL has been developed as a sequential-delivery tablet formulation combining an immediate release esomeprazole magnesium layer and an enteric coated delayed-release naproxen core. As a result, esomeprazole is released in the stomach prior to the dissolution of naproxen in the small intestine. The enteric coating prevents naproxen release at pH levels below 5 providing protection against possible local gastric toxicity of naproxen.
Due to the delayed-release of naproxen, VIVIDOL is not intended for, and has not been studied in, acute pain.
Naproxen is a NSAID with analgesic and antipyretic properties. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
Esomeprazole is the S-enantiomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+K+-ATPase – the acid pump and inhibits both basal and stimulated acid secretion.
Pharmacodynamic effects
Effect on gastric acid secretion
An optimal effect (maintenance of high gastric pH) was achieved with VIVIDOL formulation containing 20 mg of esomeprazole. After 9 days of dosing twice daily with VIVIDOL, intragastric pH above 4 was maintained for a mean time of 17.1 hours (SD 3.1) in healthy volunteers. The corresponding value for NEXIUM 20 mg was 13.6 hours (SD 2.4).
Other effects related to acid inhibition
During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
An increased number of enterochromaffin-like (ECL) cells possibly related to the increased serum gastrin levels, have been observed in some patients during long-term treatment with esomeprazole. The findings are considered to be of no clinical significance.
During long-term treatment with antisecretory drugs gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalised patients, possibly also Clostridium difficile.
Pharmacokinetics:
Absorption
Naproxen
After single dose application the time to peak plasma concentration is achieved after 3 to 5 hours, however, food intake results in further delay up to 8 hours or more. At steady state following administration of VIVIDOL twice daily, peak plasma concentrations of naproxen are reached within a median time of 3 hours following both the morning and the evening dose.
Bioequivalence between VIVIDOL and enteric-coated naproxen, based on both area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of naproxen, has been demonstrated.
Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%.
Steady-state levels of naproxen are reached in 4 to 5 days.
Esomeprazole
Following administration of VIVIDOL twice daily, esomeprazole is rapidly absorbed with peak plasma concentration reached within a median time of 0.5-0.75 hours following the morning and evening dose on both the first day of administration and at steady state. After repeated bid dosing of VIVIDOL, the Cmax was 2-3 times higher, and the AUC 4-5 times higher, as compared to the first day of dosing. This is probably partly a result of an increased absorption due to the pharmacodynamic effect of esomeprazole with increased intragastric pH, leading to reduced acid degradation of esomeprazole in the stomach. A decrease of first pass metabolism and systemic clearance of esomeprazole with repeated dosing also contributes to the higher plasma concentrations at steady state (see Linearity/non-linearity).
Even though the AUC range at steady state was comparable for NEXIUM 20 mg once daily and VIVIDOL twice daily: 292.0 – 2279.0 ng/ml and 189.0 – 2931.0 ng/ml, respectively, the mean exposure was 60% higher (CI: 1.28 – 1.93) for VIVIDOL. This could be expected due to the different total dose of esomeprazole given as VIVIDOL or NEXIUM (40 versus 20 mg). Cmax was 60% higher (CI: 1.27 – 2.02), for VIVIDOL, which was expected for an IR formulation.
Concomitant administration with food
Administration of VIVIDOL together with food does not affect the extent of absorption of naproxen but significantly delays the absorption by about 8 hours and decreases peak plasma concentration by about 12%.
Administration of VIVIDOL together with food does not delay the absorption of esomeprazole but significantly reduces the extent of absorption, resulting in 52% and 75% reductions of area under the plasma concentration versus time curve and peak plasma concentration, respectively.
Administration of VIVIDOL 30 minutes before food intake has only minimal or no effect on the extent and time to absorption of naproxen and has no significant effect on the rate or extent of esomeprazole absorption compared to administration under fasted conditions.
Elimination
Naproxen
Following administration of VIVIDOL twice daily, the mean elimination half-life for naproxen is approximately 9 hours and 15 hours following the morning and evening dose, respectively, with no change with repeated dosing.
The clearance of naproxen is 0.13 ml/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (< 1%), 6-0-desmethyl naproxen (< 1%) or their conjugates (66% to 92%). Small amounts, 3% or less of the administered dose, are excreted in the faeces. In patients with renal failure metabolites may accumulate.
Esomeprazole
Following administration of VIVIDOL twice daily, the mean elimination half-life for esomeprazole is approximately 1 hour following both the morning and evening dose on day 1, with a slightly longer elimination half-life at steady state (1.2-1.5 hours).
Total plasma clearance of esomeprazole is about 17 l/h after a single dose and about 9 l/h after repeated administration.
Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in urine.
Linearity/non-linearity
Naproxen
At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36.5, 49.2 and 56.4 mg/l with 500, 1000 and 1500 mg daily doses of naproxen, respectively).
Esomeprazole
The area under the plasma esomeprazole concentration-time curve increases with repeated administration of VIVIDOL. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time- and dose-dependency is partly due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite. An increased absorption of esomeprazole with repeated administration of VIVIDOL probably also contributes to the time-and dose-dependency (see Absorption).
Hepatic impairment
The pharmacokinetics of VIVIDOL has not been determined in patients with impaired hepatic function.
Naproxen: The pharmacokinetics of naproxen has not been determined in subjects with hepatic impairment.
Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for the naproxen component of VIVIDOL dosing is unknown but it is prudent to use the lowest effective dose.
Esomeprazole: The metabolism of esomeprazole in patients with mild to moderate hepatic impairment may be impaired. The metabolic rate is decreased in patients with severe hepatic impairment resulting in a doubling of the area under the plasma concentration-time curve of esomeprazole.
Patients with severe hepatic insufficiency should not receive VIVIDOL.
Elderly
There is no specific data on the pharmacokinetics of VIVIDOL in patients over age 65.
Naproxen: Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in older people, however the unbound fraction is < 1% of the total naproxen concentration. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some older patients.
Esomeprazole: The metabolism of esomeprazole is not significantly changed in older subjects (71-80 years of age).
Distribution
Naproxen
Naproxen has a volume of distribution of 0.16 l/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma.
Esomeprazole
The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 l/kg body weight. Esomeprazole is 97% plasma protein bound.
Biotransformation
Naproxen
30% of naproxen is metabolized in the liver by the cytochrome P450 system (CYP), primarily CYP2C9, to 6–0–desmethyl naproxen. Neither the parent drug nor the metabolites induce metabolizing enzymes. Both naproxen and 6–0–desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites.
Esomeprazole
Esomeprazole is completely metabolised by the CYP system. The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma. The major metabolites of esomeprazole have no effect on gastric acid secretion.
Special populations
Renal impairment
The pharmacokinetics of VIVIDOL has not been determined in patients with renal impairment.
Naproxen: Naproxen pharmacokinetics has not been determined in subjects with renal impairment.
Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. VIVIDOL is contraindicated for use in patients with severe renal impairment (creatinine clearance < 30 ml/min).
Esomeprazole: No studies have been performed with esomeprazole in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Poor CYP2C19 metabolisers
Esomeprazole: Approximately 3% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were about 60% higher.
These findings have no implications for the posology of VIVIDOL.
Gender
Esomeprazole: Following a single dose of 40 mg esomeprazole the mean area under the plasma concentration-time curve is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. These findings have no implications for the posology of VIVIDOL.
Presentation:
Box of 3 blisters x 10 tablets.
Storage conditions, shelf – life, quality specification of the medicine:
Storage conditions: Protect from humidity and light, below 300C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house.
A1202078801
