Vimovo - Package Leaflet
Active ingredients: Naproxen, Esomeprazole
VIMOVO 500 mg / 20 mg modified release tablets
Indications Why is Vimovo used? What is it for?
What is VIMOVO
VIMOVO contains two different medicines called naproxen and esomeprazole. Each of these medicines works differently.
- Naproxen belongs to a group of medicines called "Non-Steroidal Anti-Inflammatory Drugs" (NSAIDs). Reduces pain and inflammation.
- Esomeprazole belongs to a group of medicines called 'proton pump inhibitors'. It reduces the amount of acid in the stomach.
Esomeprazole helps reduce the risk of developing ulcers and stomach problems in patients taking NSAIDs.
What is VIMOVO for
VIMOVO is used to relieve the symptoms of:
- Rheumatoid arthritis.
- Ankylosing spondylitis.
VIMOVO helps relieve pain, swelling, redness and heat (inflammation).
This drug will be given to you if it is considered likely that a lower dose of NSAIDs will not be effective in relieving pain and if you are at risk of developing an ulcer in the stomach or in the first part (duodenum) of the small intestine when taking NSAIDs.
Contraindications When Vimovo should not be used
Do not take VIMOVO if:
- He is allergic (hypersensitive) to naproxen.
- You are allergic to esomeprazole or other proton pump inhibitor medicines.
- You are allergic to any of the other ingredients of VIMOVO (listed in Section 6: Further information).
- You are taking a medicine called "atazanavir" or "nelfinavir" (used to treat HIV).
- Acetylsalicylic acid (eg aspirin), naproxen or other NSAIDs such as ibuprofen, diclofenac or COX-2 inhibitors (eg celecoxib, etoricoxib) have caused you asthma (difficulty breathing) or an allergic reaction such as itching or skin rash (hives).
- It is in the last 3 months of pregnancy.
- You have severe liver, kidney or heart problems.
- You have an "ulcer in the stomach or intestines".
- You have a severe, sudden bleeding disorder or bleeding.
Do not take VIMOVO if you have any of the conditions listed above. If in doubt, consult your doctor or pharmacist before taking VIMOVO.
Precautions for use What you need to know before you take Vimovo
Do not take VIMOVO and see your doctor straight away if any of the events listed below occur before or while taking VIMOVO, as this medicine may hide the symptoms of other diseases:
- You lose a lot of weight for no reason and have difficulty swallowing.
- Start vomiting food or blood.
- Presence of black stools (presence of digested blood in the stool).
If any of the events listed above occur (or if you are unsure), consult your doctor or pharmacist before taking this medicine. Consult your doctor or pharmacist before taking this medicine if:
- You have intestinal inflammation (Crohn's disease or ulcerative colitis).
- You have any other liver or kidney problems or are elderly.
- You are taking medicines such as oral corticosteroids, warfarin, selective serotonin reuptake inhibitors (SSRIs), acetylsalicylic acid (aspirin) or NSAIDs including COX-2 inhibitors (see section Taking other medicines).
If any of the events listed above occur (or if you are unsure), consult your doctor or pharmacist before taking this medicine.
If you have ever had an "ulcer or" stomach bleeding, please tell your doctor. You will be asked to report any unusual stomach symptoms (e.g. pain) to your doctor
Medicines such as VIMOVO may be associated with a minimal increased risk of heart attack (myocardial infarction) or stroke. The risk is more likely with high doses and long-term treatment. Do not exceed the recommended dose or duration of treatment.
The use of VIMOVO in children is not recommended.
Also, consult your doctor before taking this medicine if you have heart problems, have had a stroke or if you think you may be at risk for any of these problems. You may be at risk for any of these problems if:
- You have high blood pressure.
- You have blood circulation or blood clotting problems.
- He has diabetes.
- He has high cholesterol.
- He is a smoker.
Interactions Which drugs or foods can change the effect of Vimovo
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines such as those obtained without a prescription, including herbal products. This is because VIMOVO can affect the way other medicines work. Also, other medicines can affect the way VIMOVO works.
Do not take this medicine and tell your doctor or pharmacist if you are taking:
- a medicine called "atazanavir" or "nelfinavir" (used in the treatment of HIV). Tell your doctor or pharmacist if you are taking any of the following medicines:
- Acetylsalicylic acid (aspirin). If you take low-dose aspirin you can continue to take VIMOVO.
- Other NSAID medicines (including COX-2 inhibitors).
- Some medicines such as ketoconazole, itraconazole, posaconazole or voriconazole (used to treat infections caused by fungi).
- Erlotinib (or other cancer drugs of the same class).
- Cholestyramine (used to lower cholesterol).
- Clarithromycin (used to treat infections).
- Quinolone antibiotics (for infections) such as ciprofloxacin or moxifloxacin.
- Diazepam (used in the treatment of anxiety, to relax muscles or used in the treatment of epilepsy).
- Idantoins as well as phenytoin (used in the treatment of epilepsy).
- Lithium (used in the treatment of some types of depression).
- Methotrexate (used in the treatment of rheumatoid arthritis, psoriasis and cancers).
- Probenecid (for gout).
- "Selective serotonin reuptake inhibitors" (SSRIs) (used in the treatment of severe depression and anxiety disorders).
- Ciclosporin or tacrolimus (medicines used to reduce the body's immune reactions).
- Digoxin (used in the treatment of heart ailments).
- Sulfonylureas such as glimepiride (oral medicines used in diabetic patients to control blood sugar levels).
- Medicines used in the treatment of high blood pressure called diuretics (such as furosemide or hydrochlorothiazide), ACE inhibitors (such as enalapril) and beta blockers (such as propranolol).
- Corticosteroid medicines such as hydrocortisone or prednisolone (used as anti-inflammatory medicines).
- Medicines used to block blood clotting, such as warfarin, dicumarol, heparin or clopidogrel.
- Rifampicin (used to treat tuberculosis).
- St. John's wort (Hypericum perforated) (used to treat mild depression).
- Cilostazol (used for leg pain due to poor blood flow).
If any of the events listed above occur (or if you are unsure), consult your doctor or pharmacist before taking VIMOVO.
Taking VIMOVO with food and drink
Do not take VIMOVO with food. This may reduce the effect of VIMOVO. Take the tablets at least 30 minutes before meals.
Warnings It is important to know that:
Pregnancy and breastfeeding
- Do not take VIMOVO if you are in the last 3 months of pregnancy.
- Consult your doctor before taking this medicine if you are in the first or second trimester of pregnancy. Your doctor will decide whether you can take VIMOVO.
- Do not breast-feed if you are taking VIMOVO. This is because small amounts of the medicine can pass into breast milk. If you intend to breastfeed, you must not take VIMOVO.
Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant, might become pregnant or breastfeeding. VIMOVO can make conception more difficult. Tell your doctor if you are planning to become pregnant or have problems conceiving.
Driving and using machines
You may feel dizzy or blurred while taking VIMOVO. If this happens, do not drive or use any tools or machines.
Important information about some of the ingredients of VIMOVO
VIMOVO contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216), which can cause allergic reactions. These reactions may not occur immediately
Dose, Method and Time of Administration How to use Vimovo: Posology
Always take VIMOVO exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Taking this medicine
- Swallow the tablets whole with a drink of water. You should not chew, divide or crush the tablets. It is important to take the tablets whole for the medicine to work properly.
- Take the tablets at least 30 minutes before meals.
- If you take this medicine for a long time, your doctor will want to monitor you (especially if you take it for more than a year).
Quantity to take
- Take one tablet twice a day for the length of time your doctor has told you.
- VIMOVO is only available in the 500 mg / 20 mg strength. If your doctor thinks this dose is not suitable for you, he may prescribe another therapy.
Overdose What to do if you have taken too much Vimovo
If you take more VIMOVO than you should
If you take more VIMOVO than you should, tell your doctor or pharmacist straight away. Symptoms of overdose may include dizziness, sleepiness, upper abdominal pain and / or malaise, heartburn, nausea, confusion, vomiting, stomach or bowel bleeding, loss of consciousness, severe swelling of the face, allergic reactions and involuntary body movements.
If you forget to take VIMOVO
- If you forget to take a dose, take it as soon as you remember to do so.However, if it is almost time for the next dose, skip the missed dose.
- Do not take a double dose (two doses at the same time) to make up for a forgotten dose.
Side Effects What are the side effects of Vimovo
Like all medicines, VIMOVO can cause side effects, although not everybody gets them. The following side effects may occur with this medicine.
Stop taking VIMOVO and see a doctor immediately if you notice any of the serious side effects, as you may need urgent medical attention:
- Sudden wheezing, swelling of the lips, tongue and throat or body, rash, fainting or difficulty swallowing (severe allergic reaction).
- Redness of the skin with blistering or peeling. There may also be severe blistering and bleeding in the lips, eyes, mouth, nose and genitals.
- Yellowing of the skin or whites of the eyes, dark urine and tiredness which can be symptoms of liver problems.
- Medicines such as VIMOVO may be associated with a minimal increased risk of heart attack (myocardial infarction) or stroke. Signs include chest pains extending to the neck and shoulders and spreading to the left arm, a feeling of confusion or muscle weakness, or numbness that may be on one side of the body only.
- Presence of black sticky stools or bloody diarrhea.
- Vomits blood or dark particles that look like coffee grounds.
Tell your doctor as soon as possible if you experience any of the following symptoms:
VIMOVO can in rare cases interfere with the number or function of white blood cells, resulting in an immune deficiency.
If you have an "infection with symptoms such as fever with severe worsening of your general condition or fever with symptoms of local infection such as pain in the neck, throat or mouth, or difficulty urinating, you should see your doctor as soon as possible so that you can rule out a lack of white blood cells (agranulocytosis) with a blood test It is important for you to provide information about your medicine at this time.
Other possible side effects include:
Common (affects 1 to 10 users in 100)
- Increased sweating.
- Itchy skin and rashes.
- Dizziness (vertigo).
- Red or purple marks, bruises or spots on the skin.
- Nausea or vomiting.
- Fast and light beats of the heart (palpitations).
- Disturbed sleep or difficulty sleeping (insomnia).
- Hearing problems such as ringing in the ears.
- Dizziness, sleepiness or lightheadedness.
- Swelling in the hands, feet and ankles (edema).
- Inflammation inside the mouth, pain in the mouth or mouth ulcers.
- Vision problems, such as blurred vision, conjunctivitis or eye pain.
- Diarrhea, stomach pains, heartburn, indigestion, constipation, belching or bloating (flatulence
Uncommon, rare or very rare (affects 1 to 10 users in 1,000 or less)
- Dry mouth
- Loss of hearing.
- Asthma attack.
- Convulsions or seizures.
- Menstrual cycle problems.
- Weight changes.
- Hair loss (alopecia).
- Raised skin rash (hives).
- Joint pain (arthralgia).
- Breast enlargement in men.
- Sore or swollen tongue.
- Involuntary movements or muscle tremors.
- Problems with appetite or changes in taste.
- Muscle weakness or pains (myalgia).
- Blood clotting may take longer than normal.
- Problems with conception in women.
- Fever, redness, or other signs of infection.
- Irregular, slow or very fast heartbeat.
- Difficulty with memory or concentration.
- Agitation, confusion, anxiety or restlessness.
- General feeling of malaise, weakness and lack of energy.
- Swollen or painful body parts due to increased water retention.
- High or low blood pressure. You may feel about to faint or feel dizzy.
- Rashes or blisters, or the skin becomes more sensitive to sun exposure.
- Seeing, feeling or hearing things that are not there (hallucinations).
- Changes in the results of blood tests, such as those to check liver function. Your doctor will be able to explain them in detail.
- An infection called "candidiasis" which can affect the digestive system and is caused by a fungus.
- Blood in your urine or other kidney problems. You may experience back pain.
- Difficulty in breathing, which may slowly get worse. This may be a symptom of pneumonia or ongoing swelling of the lungs.
- Low levels of salt (sodium) in the blood. This can cause weakness, vomiting and cramps.
- symptoms of meningitis such as fever, nausea or vomiting, stiff neck, headache, sensitivity to bright light and confusion.
- Problems with the pancreas. Symptoms include severe stomach pain that extends to the back.
- Pale colored stools which are a symptom of severe liver problems (hepatitis). Severe liver problems can lead to liver failure and brain inflammation.
- Worsening of intestinal inflammation such as Crohn's disease or ulcerative colitis. Symptoms include pain, diarrhea, vomiting, and weight loss.
- Blood problems, such as a lower number of red blood cells (anemia), white blood cells or platelets. This can cause weakness, bruising, fever, severe tremors, sore throat, or can make you more vulnerable to infection.
- Problems with the way the heart pumps blood around the body or damage to blood vessels. Symptoms can include fatigue, wheezing, feeling faint, chest pains or aches in general.
- Low levels of magnesium in the blood (hypomagnesaemia). You may not have any symptoms unless your levels are very low. In this case, confusion, muscle weakness or cramps, irregular heartbeats or seizures can occur.
Don't worry about this list of possible side effects. It is possible that none will appear.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Keep VIMOVO out of the reach and sight of children.
Do not use VIMOVO after the expiry date which is stated on the carton, bottle or blister after EXP. The expiry date refers to the last day of the month.
Do not store above 30 ° C.
Bottle: Store in the original package and keep the bottle tightly closed to protect from moisture.
Blisters: Store in the original package to protect from moisture.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
What VIMOVO contains
- The active ingredients are naproxen 500 mg and esomeprazole 20 mg.
- The other ingredients in the tablet core are croscarmellose sodium, magnesium stearate, povidone, colloidal silica dioxide, and in the coating film are carnauba wax, glycerol monostearate 40-55, hypromellose, iron oxide (E172, yellow, black), macrogol 8000 , methacrylic acid-ethyl acrylate copolymer, methyl parahydroxybenzoate (E218), polydextrose, polysorbate 80, propylene glycol, propyl parahydroxybenzoate (E216), sodium lauryl sulfate, titanium dioxide (E171), triethyl citrate
Description of the appearance of VIMOVO and contents of the pack
They are oval, yellow tablets marked 500/20 in black ink.
Pack sizes - 6, 20, 30, 60, 100, 180 or 500 modified release tablets. The bottles contain silica gel desiccants (to keep the tablets dry).
Packaging in aluminum blister:
Pack sizes - 10, 20, 30, 60 or 100 modified release tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
VIMOVO 500 MG / 20 MG MODIFIED RELEASE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each modified-release tablet contains 500 mg of naproxen and 20 mg of esomeprazole (as magnesium trihydrate).
Excipients with known effects:
VIMOVO contains very low, non-protective amounts of 0.02 mg of methyl parahydroxybenzoate and 0.01 mg of propyl parahydroxybenzoate (see sections 4.4 and 6.1).
For the full list of excipients, see section 6.1.
03.0 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.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
VIMOVO is indicated in adults for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, in patients at risk of developing gastric and / or duodenal ulcers associated with treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and in cases where treatment with lower than naproxen or other NSAIDs is not considered sufficient.
04.2 Posology and method of administration
The recommended dose is 1 tablet (500 mg / 20 mg) twice a day.
Undesirable effects of naproxen can be minimized by using the lowest effective dose for the shortest possible period (see section 4.4). In patients not previously treated with NSAIDs, a lower daily dose of naproxen or another NSAID should be considered. For this purpose, non-fixed association products are available. When the total daily dose of 1,000 mg naproxen is not considered adequate (500 mg twice daily), alternative treatments with lower doses of naproxen or other non-fixed combination NSAIDs should be used.
Treatment should be continued until individual treatment goals are achieved, should be reviewed at regular intervals, and should be discontinued if no benefit or worsening.
Due to the delayed release of naproxen from the enteric-coated formulation (3-5 hours), VIMOVO is not intended for the rapid relief of acute pain conditions (such as dental pain). However, flare-ups of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis can be treated with VIMOVO.
Patients with renal insufficiency
In patients with mild to moderate renal impairment VIMOVO should be used with caution and renal function should be closely monitored. A reduction in the total daily dose of naproxen should be considered (see sections 4.4 and 4.5). When the total daily dose of 1,000 mg of naproxen is not considered adequate (500 mg twice daily), alternative treatments with lower doses of naproxen or other non-fixed combination NSAIDs should be used, and the need should also be reassessed. to continue gastroprotective treatment.
VIMOVO is contraindicated in patients with severe renal insufficiency (creatinine clearance
Patients with hepatic insufficiency
In patients with mild to moderate hepatic impairment VIMOVO should be used with caution and liver function should be closely monitored. A reduction in the total daily dose of naproxen should be considered (see sections 4.4 and 5.2). When the total daily dose of 1,000 mg naproxen is not considered adequate (500 mg twice daily), alternative treatments with lower doses of naproxen or other non-fixed combination NSAIDs should be used, and the need to continue gastroprotective treatment.
VIMOVO is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2).
Older people (> 65 years)
Elderly people are at an increased risk of serious consequences from adverse reactions (see sections 4.4 and 5.2). When the total daily dose of 1,000 mg naproxen (500 mg twice daily) is not considered adequate (e.g. in elderly people with impaired renal function or low body weight), alternative treatments with lower doses of naproxen should be used. or other non-fixed combination NSAIDs, and the need for continued gastroprotective treatment should also be re-evaluated.
Pediatric population (≤18 years)
The safety and efficacy of VIMOVO in children aged 0-18 years have not been established. No data are available.
Method of administration
The VIMOVO tablet must be swallowed whole with a little water and must not be divided, chewed or crushed.
It is recommended to take VIMOVO at least 30 minutes before meals (see section 5.2).
• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or to substitutes benzimidazoles
• History of asthma, urticaria or allergic-type reactions induced by administration of acetylsalicylic acid or other NSAIDs (see section 4.4)
• Third trimester of pregnancy (see section 4.6)
• Severe liver failure (eg Child-Pugh C)
• Severe heart failure
• Severe renal insufficiency
• Active peptic ulcer (see section 4.4, Gastrointestinal effects, Naproxen)
• Gastrointestinal haemorrhage, cerebrovascular haemorrhage 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).
04.4 Special warnings and appropriate precautions for use
The combination of VIMOVO with other NSAIDs including selective cyclooxygenase-2 inhibitors should be avoided due to the cumulative risks of inducing serious NSAID-related adverse events. VIMOVO, can be used in patients being treated with low dose acetylsalicylic acid (see also section 4.5.).
Undesirable effects can be minimized by using the lowest effective dose for the shortest duration possible to control symptoms (see section 4.2, and gastrointestinal and cardiovascular effects below).
To avoid overtreatment, the prescribing physician should assess at clinically meaningful intervals, based on individual risks and based on the characteristics and severity of the underlying disease being treated, whether sufficient pain control with lower doses of NSAIDs is possible in non-fixed associations.
When the total daily dose of 1,000 mg naproxen (500 mg twice daily) is not considered adequate, alternative treatments with lower doses of naproxen or other non-fixed combination NSAIDs should be used, and the need should be reassessed. to continue gastroprotective treatment.
Risk factors for the development of gastrointestinal complications associated with NSAID treatment include advanced age, concomitant use of anticoagulants, corticosteroids, other NSAIDs including low-dose acetylsalicylic acid, debilitating cardiovascular disease, infection withHelicobacter pylori, as well as a history of gastric and / or duodenal ulcer and upper gastrointestinal bleeding.
In patients suffering from the following conditions, naproxen should only be used after a rigorous risk / benefit assessment:
• Induced porphyrias
• Systemic lupus erythematosus and undifferentiated connective tissue disease, since rare cases of aseptic meningitis have been described in these patients.
Patients on long-term treatment (particularly those on treatment for more than one year) should be monitored periodically.
VIMOVO contains very low levels of methyl and propyl parahydroxybenzoate, which may cause allergic reactions (sometimes delayed) (see sections 2 and 6.1).
Naproxen: In elderly people there is an increased frequency of adverse reactions, especially gastrointestinal haemorrhage and perforation, which can be fatal (see sections 4.2 and 5.2). The esomeprazole component of VIMOVO reduced the incidence of ulcers in older people.
Naproxen: Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a "history of serious gastrointestinal events."
The risk of gastrointestinal bleeding, ulceration or perforation with NSAIDs is higher with higher doses of NSAIDs, 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 start treatment at the lowest available doses. For these patients and for patients requiring concomitant use of low dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, combination therapy should be considered. with protective agents (e.g. misoprostol or proton pump inhibitors) (see below and 4.5). The esomeprazole component of VIMOVO is a proton pump inhibitor.
Patients with a history of gastrointestinal toxicity, especially elderly people, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) especially in the early stages of treatment.
Caution is advised in patients taking NSAIDs concomitantly with medicinal products that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid (for information on the use of VIMOVO with low dose acetylsalicylic acid, see section 4.5).
Ulcer-associated complications such as haemorrhage, perforation and obstruction have not been studied in clinical studies with VIMOVO.
If gastrointestinal bleeding or ulceration occurs in patients taking VIMOVO, the treatment should be discontinued (see section 4.3).
NSAIDs should be administered with caution 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 symptoms (eg significant involuntary weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and in the event of a suspected or present gastric ulcer, malignancy should be excluded, as treatment with esomeprazole magnesium can relieve symptoms and delay diagnosis.
Dyspepsia may still occur despite the addition of esomeprazole to the tablet (see section 5.1).
Treatment with proton pump inhibitors may lead to a slightly increased risk of gastrointestinal infections, such as those fromSalmonella And Campylobacter (see section 5.1).
Esomeprazole, like all acid-suppressive medicinal products, may reduce the absorption of vitamin B12 (cyanocobalamin) following hypo- or achlorhydria. This should be taken into consideration in patients with low reserves or risk factors for reduced vitamin B12 absorption. in case of long-term therapies.
Cardiovascular and cerebrovascular effects
Naproxen: Adequate monitoring and recommendations are required for patients with a history of arterial hypertension and / or mild to moderate congestive heart failure as fluid retention and edema have been reported in association with NSAID therapy.
Clinical study and epidemiological data suggest that the use of coxibs and some NSAIDs (especially at high doses and in long-term treatments) may be associated with a slightly increased risk of arterial thrombotic events (eg myocardial infarction or stroke) Although the data suggest that the use of naproxen (1,000 mg per day) may be associated with a lower risk, a certain risk cannot be excluded.
Patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and / or cerebrovascular disease should only be treated with naproxen after careful consideration. A similar consideration should be made before initiating long-term treatment in patients with risk factors for cardiovascular events (eg arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).
Naproxen: Long-term administration of NSAIDs resulted in renal papillary necrosis and other renal lesions. Renal toxicity has also been observed in patients in whom prostaglandins have a compensatory role in maintaining renal perfusion. In these patients, NSAID administration may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which can precipitate overt renal failure. Patients at greatest risk of this reaction are patients with impaired renal function, hypovolaemia, heart failure, liver dysfunction, electrolyte disturbance, patients taking diuretics, angiotensin converting enzyme inhibitors (ACE inhibitors) or antagonists of angiotensin receptor II and the elderly. Discontinuation of NSAID therapy is usually followed by a return to the pretreatment state (see also below, and sections 4.2 and 4.5).
Use in patients with impaired renal function
Since naproxen and its metabolites are eliminated for the most part (95%) by urinary excretion via glomerular filtration, it should be used with great caution in patients with impaired renal function and monitoring of serum creatinine and / or serum creatinine is recommended in these patients. creatinine clearance. The use of VIMOVO is contraindicated in patients with a baseline creatinine clearance below 30 ml / minute (see section 4.3).
Hemodialysis does not decrease the plasma concentration of naproxen due to the high degree of binding to plasma proteins.
Certain patients, particularly those whose renal blood flow is impaired due to extracellular volume depletion, liver cirrhosis, sodium restriction, congestive heart failure and pre-existing kidney disease, should undergo evaluation of renal function before and during therapy with VIMOVO. Some elderly people in whom renal function is expected to be impaired, as well as patients taking diuretics, ACE inhibitors or angiotensin receptor II antagonists are included in this category. A reduction in daily dosage should be considered to avoid the possibility. of excessive accumulation of naproxen metabolites in these patients.
Borderline elevations of one or more liver function tests may occur in patients taking NSAIDs. Liver abnormalities may be the result of hypersensitivity rather than direct toxicity. There have been rare reports of severe hepatic reactions, including jaundice, fulminant hepatitis with a fatal course, hepatic necrosis and hepatic failure, some with fatal outcomes.
The use of NSAIDs may be associated with acute renal failure in patients with severe liver cirrhosis. These patients also frequently suffer from coagulopathy related to inadequate synthesis of coagulation factors. Antiplatelet effects related to naproxen may further increase the risk of serious bleeding in these patients.
Naproxen: Patients with bleeding disorders or receiving drug therapy that interferes with haemostasis should be closely monitored when administering products containing naproxen.
Patients at high risk of haemorrhage and patients on full anticoagulant therapy (e.g. dicumarol derivatives) may be at increased risk of haemorrhage when taking concomitant products containing naproxen (see section 4.5).
Naproxen decreases platelet aggregation and prolongs bleeding time. This effect should be taken into account when determining bleeding times.
When “active and clinically significant bleeding” occurs in patients taking VIMOVO, whatever the cause, treatment should be stopped.
Naproxen: Due to adverse ophthalmic effects in animal studies with NSAIDs, it is recommended that an ophthalmologic examination be performed in the event that any visual impairment or disturbance occurs.
Naproxen: Serious skin reactions, some 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 maximally exposed. risk of these reactions at the start of therapy, since in the majority of cases the reactions occur within the first month of treatment. VIMOVO should be discontinued at the first occurrence of skin rash, mucosal lesions or any other sign of hypersensitivity.
Anaphylactic (anaphylactoid) reactions
Naproxen: Hypersensitivity reactions can occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions can occur in patients with and without a history of hypersensitivity or exposure to acetylsalicylic acid, other NSAIDs, or products containing naproxen. They may also occur in individuals with a "history of angioedema, bronchospastic reactivity (eg asthma), rhinitis, and nasal polyps."
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 patients sensitive to acetylsalicylic acid , VIMOVO should not be administered to patients with this form of sensitivity to acetylsalicylic acid (see section 4.3) and should be used with caution in patients with pre-existing asthma.
Naproxen: The antipyretic and anti-inflammatory activities of naproxen can reduce fever and other signs of inflammation, thereby diminishing their usefulness as diagnostic signs.
The use of VIMOVO, as with any other drug known to inhibit cyclooxygenase / prostaglandin synthesis, may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or who are undergoing infertility testing, discontinuation of VIMOVO should be considered (see section 4.6).
Combination with other medicinal products:
Co-administration of atazanavir and proton pump inhibitors is not recommended (see section 4.5). If the combination of atazanavir and proton pump inhibitor is judged unavoidable, careful clinical monitoring (eg viral load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; the dose of esomeprazole should not exceed 20 mg and therefore VIMOVO should not be used concomitantly with atazanavir (see section 4.3).
Esomeprazole is a CYP2C19 inhibitor. Potential interaction with drugs metabolised by CYP2C19 should be considered at initiation or termination of treatment with esomeprazole. An interaction between clopidogrel and esomeprazole has been observed (see section 4.5). The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of clopidogrel and esomeprazole should be discouraged.
Proton pump inhibitors (PPIs) such as esomeprazole have been shown to cause severe hypomagnesaemia in patients treated for at least three months and in many cases for one year. Serious symptoms of hypomagnesaemia include fatigue, tetany, delirium, convulsions, dizziness, and ventricular arrhythmia. They can initially manifest insidiously and be neglected. Hypomagnesaemia in most patients improves after taking magnesium and discontinuing the proton pump inhibitor. Healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment. treatment in patients on therapy for a long time or on digoxin therapy or medicines that can cause hypomagnesaemia (e.g. diuretics).
Proton pump inhibitors, especially when used in high doses and for prolonged periods (> 1 year), may cause a slightly increased risk of hip, wrist and spine fractures, especially in older people or in the presence of other known risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fracture by 10% to 40%. This increase may be partly due to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical practice guidelines and must take an "adequate amount of vitamin D and calcium.
04.5 Interactions with other medicinal products and other forms of interaction
Contraindications to concomitant use (see section 4.3)
Interactions have been reported between omeprazole, the racemic D + S omeprazole (esomeprazole), and some antiretroviral drugs. The clinical relevance and mechanisms of these interactions are not always known. The increase in gastric pH during omeprazole treatment may alter the absorption of the antiretroviral drug. Other possible mechanisms of interaction occur through CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given with omeprazole. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg / 100 mg ritonavir in healthy volunteers results in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax and Cmin). An increase in the atazanavir dose to 400 mg does not compensate for the impact of omeprazole on atazanavir exposure. Co-administration of omeprazole (40 mg / day) reduced the mean AUC, Cmax and Cmin of nelfinavir by 36-39% and the mean AUC, Cmax and Cmin of the pharmacologically active metabolite M8 by 75-92. %.
For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported. There are also some antiretroviral drugs for which unchanged serum levels have been reported when given with omeprazole.
No interaction studies of VIMOVO with atazanavir have been conducted. However, due to the similar pharmacodynamic and pharmacokinetic properties of omeprazole and esomeprazole, concomitant use of atazanavir and nelfinavir with esomeprazole is not recommended and co-administration with VIMOVO is contraindicated. (see section 4.3).
Concomitant use with precaution
Other analgesics including selective cyclooxygenase-2 inhibitors:
The concomitant use of two or more NSAIDs should be avoided as it may increase the risk of adverse effects, particularly gastrointestinal ulcers and bleeding. The concomitant use of VIMOVO with other NSAIDs, except low dose acetylsalicylic acid (≤325 mg / day), is not recommended (see section 4.4).
VIMOVO can be administered during low dose acetylsalicylic acid therapy (≤325 mg / day). In clinical trials, there was no increase in the number of gastric ulcers in patients taking VIMOVO in combination with low dose acetylsalicylic acid compared to patients taking VIMOVO alone (see section 5.1). However, concomitant use of acetylsalicylic acid and VIMOVO may increase the risk of serious adverse events (see sections 4.4 and 4.8).
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 serum levels of tacrolimus. During treatment with VIMOVO, closer monitoring of serum tacrolimus concentration as well as renal function (creatinine clearance) should be performed and the tacrolimus dosage adjusted as necessary.
As with all NSAIDs, caution is advised when cyclosporine is co-administered due to the increased risk of nephrotoxicity.
Clinical studies, in addition to postmarketing observations, have shown that NSAIDs may reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant NSAID therapy, the patient should be closely observed for signs of renal failure, as well as to ensure diuretic efficacy (see section 4.4).
Selective Serotonin Reuptake Inhibitors (SSRIs)
Concomitant use of NSAIDs, including selective COX-2 inhibitors, and SSRIs increases the risk of gastrointestinal bleeding (see section 4.4).
There is an increased risk of gastrointestinal bleeding when corticosteroids are combined with NSAIDs, including selective COX-2 inhibitors.Caution should be exercised when NSAIDs are administered concomitantly with corticosteroids (see section 4.4).
ACE inhibitors / Angiotensin II receptor antagonists
According to some reports, NSAIDs may decrease 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 receptor II antagonists. The combination of NSAIDs, ACE inhibitors or angiotensin receptor II antagonists should be administered with caution in elderly, volume-depleted, or renal-impaired patients (see section 4.4).
NSAIDs can increase plasma levels of cardiac glycoside when co-administered with cardiac glycosides such as digoxin.
NSAIDs produced an increase in plasma lithium levels and a decrease in renal clearance of lithium. These effects have been attributed to inhibition of renal prostaglandin synthesis by NSAIDs. Therefore, when NSAIDs and lithium are administered concomitantly, subjects should be closely observed for signs of lithium toxicity.
When given with proton pump inhibitors, methotrexate levels tend to increase in some patients. NSAIDs tend to reduce the tubular secretion of methotrexate in an animal model. This may indicate that both esomeprazole and naproxen can intensify the toxicity of methotrexate. Clinical relevance is likely to be greater in patients receiving high doses of methotrexate and in patients with renal dysfunction. Caution should be used when VIMOVO is co-administered with methotrexate. Temporary suspension of VIMOVO is recommended when high doses of methotrexate are administered.
Naproxen is strongly bound to plasma albumin; therefore it has a theoretical potential for interaction with other drugs that bind to albumin such as sulfonylureas and hydantoins. Patients given simultaneous naproxen and a "hydantoin, sulphonamide or sulphonylurea should be observed to adjust the dosage if necessary.
The results of studies in healthy subjects showed a "pharmacokinetic (PK) / pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose / 75 mg daily maintenance dose) and esomeprazole (40 mg orally daily) with consequent decrease in "exposure to the active metabolite of clopidogrel, on average by 40% and the consequent decrease in maximal inhibition (ADP induced) of platelet aggregation, on average by 14%."
In a study in healthy subjects, there was a decrease in exposure of nearly 40% of the active metabolite of clopidogrel when a fixed combined dose of 20 mg esomeprazole and 81 mg acetylsalicylic acid were administered with clopidogrel, compared to clopidogrel alone. . However, the maximum levels of inhibition (ADP induced) of platelet aggregation in these subjects were the same in both groups.
No clinical studies have been performed on the interaction between clopidogrel and the combined fixed dose of naproxen + esomeprazole (VIMOVO).
Conflicting data on the clinical implications of the PK / PD interaction of esomeprazole in terms of major cardiovascular events have been reported in clinical and observational studies. As a precaution, concomitant use of VIMOVO and clopidogrel should be discouraged (see section 4.4).
Anticoagulants and inhibitors of platelet aggregation
NSAIDs may enhance the effects of oral anticoagulants (eg warfarin, dicumarol), heparins and inhibitors of platelet aggregation (see section 4.4).
Concomitant administration of 40 mg esomeprazole to warfarin-treated patients demonstrated that, despite a slight increase in the trough plasma concentration of the less potent R-isomer of warfarin, clotting times were within the accepted range. However, from post-marketing use, cases of high INR of clinical relevance have been reported during concomitant treatment with warfarin. Close monitoring is recommended at the initiation and end of treatment with warfarin or other coumarin derivatives.
Naproxen and other NSAIDs may reduce the antihypertensive effect of propranolol and other beta blockers.
Probenecid administered concomitantly with naproxen increases the plasma levels of the naproxen anion and significantly extends its plasma half-life.
Drugs with pH-dependent gastric absorption
Suppression of gastric acid secretion during treatment with esomeprazole and other PPIs may decrease or increase the absorption of drugs whose absorption is dependent on gastric pH.
As with other drugs that decrease intragastric acidity, the absorption of drugs such as ketoconazole, itraconazole, posaconazole and erlotinib may decrease during treatment with esomeprazole while the absorption of drugs such as digoxin may increase.
Concomitant treatment 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 up to 10% (up to 30% in two out of ten subjects).
More information on drug interactions
Evaluation studies on the concomitant administration of esomeprazole and naproxen (non-selective NSAID) or rofecoxib (COX-2-selective NSAID) did not identify any clinically relevant interactions.
As with other NSAIDs, concomitant administration of cholestyramine may delay the absorption of naproxen.
In healthy volunteers, concomitant administration of 40 mg esomeprazole resulted in a 32% increase in the area under the plasma concentration-time curve (AUC) and a 31% prolongation of the elimination half-life (t½), but not there was no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval, which was observed after administration of cisapride monotherapy, was not further prolonged when cisapride was administered in combination with esomeprazole (see also section 4.4).
Esomeprazole has been shown to have no clinically relevant effect on the pharmacokinetics of amoxicillin and quinidine.
Esomeprazole inhibits CYP2C19, the major metabolising enzyme of esomeprazole. Esomeprazole is also metabolised by CYP3A4. In relation to these enzymes, the following was observed:
• Co-administration of 30 mg esomeprazole resulted in a 45% reduction in clearance of the CYP2C19 substrate diazepam. The interaction is unlikely to be of clinical relevance.
• Co-administration of 40 mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients.
• Co-administration of esomeprazole and a combined CYP2C19 and CYP3A4 inhibitor, such as voriconazole, may result in more than doubled exposure of esomeprazole.
• Co-administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg twice daily), resulted in a doubled exposure (AUC) of esomeprazole.
None of these cases require adjustment of the esomeprazole dosage.
Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's wort) may lead to decreased esomeprazole serum levels through increased esomeprazole metabolism.
Omeprazole, like esomeprazole, acts as an inhibitor of CYP2C19. Omeprazole, given at doses of 40 mg to healthy subjects in a cross-over study, increased the Cmax and AUC of cilostazol by up to 18% and 26%, respectively, and one of its active metabolites by up to 29% and 69, respectively. %.
Animal data indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. There may be an increased risk of developing seizures in patients who are taking quinolones.
Drug / laboratory test interaction
Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be taken into account when determining bleeding times.
Administration of naproxen may result in higher urinary values of 17-ketogenic steroids due to an "interaction between the drug and / or its metabolites with m-di-nitrobenzene, which is used for this assay. Although apparently the values of 17 -hydroxy-corticosteroid (Porter-Silber test) are not altered, it is advisable to temporarily suspend naproxen therapy 72 hours before carrying out the adrenal function tests, in case the Porter-Silber test is used.
Naproxen may interfere with some urinary dosages of 5-hydroxy indolacetic acid (5HIAA).
04.6 Pregnancy and breastfeeding
Inhibition of prostaglandin synthesis may adversely affect pregnancy and / or embryo / fetal development. Data from epidemiological studies suggest an increased risk of spontaneous abortion and cardiac malformation and gastroschisis after use of a synthesis inhibitor. of prostaglandins in early pregnancy. The absolute risk of cardiac malformation increased from less than 1% 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-fetal lethality. In addition, an increased incidence of various malformations, including cardiovascular ones, has been reported in animals administered a prostaglandin synthesis inhibitor during the organogenetic period (see section 5.3).
In women attempting to become pregnant or during the first and second trimester of pregnancy, VIMOVO should not be given unless the potential benefit to the patient outweighs the potential risk to the fetus. If VIMOVO is used by a woman planning to conceive or during the first and second trimester of pregnancy, the duration of treatment should be as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors can expose the fetus to:
• cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
• renal dysfunction, which can progress to renal failure with oligo-hydroamniosis;
the mother and the newborn, at the end of pregnancy, to:
• possible prolongation of the bleeding time, an antiplatelet effect which can occur even at very low doses.
• inhibition of uterine contractions, which causes delayed or prolonged labor.
Consequently, VIMOVO is contraindicated during the third trimester of pregnancy (see section 4.3).
There is a limited amount of data on the use of esomeprazole in pregnant women. With omeprazole racemic mixture, data from epidemiological studies on a larger number of treatment-exposed pregnancies do not indicate the presence of malformative or foetotoxic effects. Animal studies with esomeprazole do not indicate direct or indirect harmful effects on embryo / fetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development.
Naproxen is excreted in human milk in small quantities. It is not known whether esomeprazole is excreted in human milk. A published case report on omeprazole racemic mixture indicated the excretion of low amounts in human milk (weight adjusted dose
The use of NSAIDs such as naproxen may impair female fertility. The use of VIMOVO is not recommended in women attempting to conceive (see section 4.4).
04.7 Effects on ability to drive and use machines
VIMOVO has minor effects on the ability to drive or use machines; on the basis of this it must be taken into account that some of the adverse effects (eg dizziness) reported following the use of VIMOVO may reduce the ability to react.
04.8 Undesirable effects
Summary of the safety profile
Immediate-release esomeprazole has been included in the tablet formulation to reduce the incidence of gastrointestinal side effects caused by naproxen. VIMOVO has been shown to significantly reduce gastric ulcers and upper gastrointestinal adverse events associated with NSAIDs. compared to naproxen alone (see section 5.1).
There were no new data on the safety profile during treatment with VIMOVO in the overall population evaluated in clinical trials (n = 1157) compared to the established safety profiles of the individual active substances naproxen and esomeprazole.
Tabulated summary of adverse reactions
Adverse reactions have been 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
The following adverse reactions were reported in patients who took VIMOVO during clinical trials.
* as noted by scheduled routine endoscopy
The following adverse reactions have been reported in patients taking naproxen during clinical trials and through postmarketing reports.
The following adverse drug reactions have been identified or suspected during the enteric-coated esomeprazole clinical trial program and / or in post-marketing use. None have been identified as dose related.
Description of certain adverse reactions
Clinical studies and epidemiological data suggest that the use of coxibs and some NSAIDs (especially at high doses and in long-term treatments) may be associated with a slightly increased risk of arterial thrombotic events (eg myocardial infarction or stroke) Although data suggest that the use of naproxen (1,000 mg per day) may be associated with a lower risk, a certain risk cannot be excluded (see section 4.4).
Edema, arterial hypertension and heart failure have been reported in association with NSAID treatment.
The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, gastrointestinal perforation or haemorrhage, sometimes fatal, may occur, particularly in the elderly (see section 4.4). Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4 - Special warnings and precautions for use) have been reported following administration of the medication Gastritis was observed less frequently.
VIMOVO was developed with esomeprazole to decrease the incidence of gastrointestinal side effects from naproxen and was shown to significantly decrease the occurrence of gastric and / or duodenal ulcers and upper gastrointestinal adverse events associated with NSAIDs compared to naproxen. in monotherapy.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
There are no clinical data on VIMOVO overdose.
Any effects of VIMOVO overdose are expected to primarily reflect the effects of naproxen overdose.
Associated with naproxen overdose
Significant overdose of naproxen may be characterized by lethargy, dizziness, somnolence, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient changes in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting.
Gastrointestinal bleeding may occur. High blood pressure, acute renal failure, respiratory depression and coma may occur, although rarely. Anaphylactoid reactions have been reported with NSAID treatment, which may occur following an overdose. Some patients experienced seizures, but it is unclear whether they were associated with the drug. It is not known what dose of the drug can be life-threatening.
Associated with esomeprazole overdose
The symptoms described in association with the voluntary overdose of esomeprazole (limited experience with doses above 240 mg / day) are transient. Single 80 mg doses of esomeprazole had no consequences.
Associated with naproxen
Patients should be managed with symptomatic and supportive therapy following NSAID overdose, particularly with regard to gastrointestinal effects and renal impairment. There are no specific antidotes.
Hemodialysis does not decrease the plasma concentration of naproxen due to the high degree of protein binding. Emesis and / or activated charcoal (60 to 100g in adults, 1 to 2g / kg in children) and / or an osmotic cathartic may be indicated in patients experiencing symptoms seen within 4 hours of ingestion or following a significant overdose. Forced diuresis, urine alkalinization or hemoperfusion may not be helpful due to high protein binding.
Associated with esomeprazole
No specific antidotes are known. Esomeprazole has a strong plasma protein binding and is therefore not readily dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be undertaken.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: naproxen and esomeprazole ATC code: M01AE52
Mechanism of action
VIMOVO was developed as sequential-release tablets, combining an immediate-release esomeprazole magnesium layer and a delayed-release enteric-coated naproxen core. Esomeprazole is then released into the stomach prior to the dissolution of naproxen in the small intestine. The enteric coating prevents the release of naproxen at pH levels below 5, providing protection against the possible local gastric toxicity of naproxen.
By virtue of the delayed release of naproxen, VIMOVO is not intended or studied for the treatment of acute pain.
Naproxen is an NSAID with analgesic and antipyretic properties. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not fully understood, but may be associated with the inhibition of prostaglandin synthetase.
Esomeprazole is the "S.-enantiomer of omeprazole and reduces gastric acid secretion through a specific and targeted mechanism of action. Esomeprazole is a weak base and is concentrated and converted to the active form in the strongly acidic environment of the secretory canaliculi of the gastric parietal cell, where it inhibits the " enzyme H + K + -ATPase - acid pumps and inhibits both basal and induced acid secretion.
Effect on gastric acid secretion
An optimal effect (maintenance of a high gastric pH) was obtained with the VIMOVO formulation containing 20 mg of esomeprazole. After 9 days of treatment with VIMOVO administered twice daily, an intragastric pH above 4 was maintained for a mean period 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 associated with acid inhibition
During treatment with antisecretory medicinal products, serum gastrin increases in response to decreased acid secretion. Chromogranin A (CgA) also increases due to the decrease in gastric acidity. The increase in CgA concentration can interfere with any investigation of endocrine tumors. Literature data report that a proton pump inhibitor must be discontinued at least 5 days before CgA measurement. If CgA and gastrin levels do not normalize after 5 days, the measurement should be repeated 14 days after the end of esomeprazole treatment.
An increase in the number of enterochromaffin-like (ECL) cells, possibly associated with increased serum gastrin levels, has been observed in some patients during long-term treatment with esomeprazole. The results are considered not clinically relevant.
During long-term treatment with antisecretory drugs, an increase in the frequency of occurrence of gastric glandular cysts was observed. These alterations are a physiological consequence of the pronounced inhibition of acid secretion, are benign and appear to be reversible.
Decreased gastric acidity by any means, including proton pump inhibitors, increases the gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to a slightly increased risk of gastrointestinal infections Salmonella And Campylobacter and possibly also from Clostridium difficile in hospitalized patients.
Clinical efficacy and safety
In clinical studies, VIMOVO was administered to a total of 491 patients for 6 months and 135 patients for 12 months.
In two randomized, double-blind, active-controlled studies, the incidence of gastric and duodenal ulcers was significantly lower after treatment with VIMOVO compared to enteric-coated naproxen 500 mg twice daily (without administration of esomeprazole or a other PPI) during a treatment period of 6 months. Participants were a priori at risk of developing NSAID-associated ulcers, due to advanced age or a history of gastric or duodenal ulcers. Patients who tested positive for H. pylorithey had been excluded from clinical trials.
The incidence of gastric ulcer for VIMOVO was 5.6%, and for enteric-coated naproxen 23.7% (6-month data from 2 endoscopic studies). VIMOVO also significantly reduced the occurrence of relative duodenal ulcers. enteric-coated naproxen (0.7 vs.5.4%) (6-month data from 2 endoscopic studies).
During these clinical trials, VIMOVO also significantly reduced the occurrence of some predetermined NSAID-associated upper gastrointestinal adverse events compared to enteric-coated naproxen (53.3% versus 70.4% (overall data).
In clinical trials with VIMOVO, only patients at risk of developing NSAID-associated gastroduodenal ulcers such as patients aged> 50 years or with uncomplicated prior ulcers were included; Patients using low-dose acetylsalicylic acid (ABD) concomitantly were also admitted to the study. Subgroup analyzes of patients confirmed a trend similar to that observed for the entire population studied with regard to efficacy in the prevention of gastrointestinal ulcer by VIMOVO. In ABD users, the incidence of gastroduodenal ulcers was of the 4.0% (95% CI 1.1-10.0%) in the VIMOVO group (n = 99) versus 32.4% (95% CI 23.4-42.3%) in the naproxen-only group EC (n = 102). In elderly people ≥ 60 years of age, the incidence of gastroduodenal ulcers was 3.3% (95% CI 1.3-6.7%) in the VIMOVO group (n = 212) compared with 30.1% ( 95% CI 24.0-36.9%) in the naproxen-only group EC (n = 209).
In two clinical trials lasting 6 months, VIMOVO reported fewer cases of upper abdominal discomfort than enteric-coated naproxen, evaluated as symptoms of dyspepsia. A significantly lower proportion of patients taking VIMOVO discontinued studies prematurely due to adverse events compared to patients taking enteric-coated naproxen alone (7.9% vs 12.5%, respectively), 4.0% and 12, 0% of the discontinuations, respectively, were due to adverse events associated with the upper digestive tract, including duodenal ulcers).
In two 12-week studies in patients with osteoarthritis of the knee, VIMOVO (500 mg / 20 mg administered twice daily) induced similar improvement in pain and function, time to onset of analgesic efficacy and study interruptions due to to adverse events similar to those observed for the celecoxib 200 mg once daily group.
The European Medicines Agency has waived the obligation to submit the results of studies with VIMOVO.
05.2 "Pharmacokinetic properties
After administration of a single dose, the time to peak plasma concentration is reached after 3-5 hours, however, food intake leads to a further delay, up to 8 hours or more.
At steady state following twice daily administration of VIMOVO, peak plasma concentrations of naproxen were achieved within a median of 3 hours following both morning and evening dosing.
Bioequivalence between VIMOVO and enteric-coated naproxen has been demonstrated, based on both the area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) of naproxen.
Naproxen is rapidly and completely absorbed in the gastrointestinal tract with a bioavailability in vivo 95%.
The steady state of naproxen is reached in 4-5 days.
After twice daily administration of VIMOVO, esomeprazole is rapidly absorbed with peak plasma concentration achieved within the mean 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 dosing of VIMOVO twice daily, the Cmax was 2-3 times higher, and the AUC 4-5 times higher, than on the first day of treatment. This is probably partly due to increased absorption due to "Pharmacodynamic effect of esomeprazole with higher intragastric pH, leading to less acid degradation of esomeprazole in the stomach. Decreased first pass metabolism and systemic clearance of esomeprazole with repeat dosing also contributes to higher steady-state plasma concentrations (see Linearity / non-linearity).
Although the steady-state AUC interval was comparable for NEXIUM 20 mg once daily and VIMOVO twice daily: 292.0 - 2279.0 ng / ml and 189.0 - 2931.0 ng / ml, respectively, " mean exposure was greater than 60% (CI: 1.28 - 1.93) for VIMOVO. This is to be expected due to the different total dose of esomeprazole administered as VIMOVO or as NEXIUM (40 versus 20 mg). Cmax was greater than 60% (CI: 1.27 - 2.02) for VIMOVO, which is expected for an IR formulation.
Concomitant administration with food
Administration of VIMOVO together with food does not affect the amount of naproxen absorption, but significantly delays absorption by approximately 8 hours and reduces the peak plasma concentration by approximately 12%.
Administration of VIMOVO together with food does not delay the absorption of esomeprazole, but significantly reduces the amount of absorption, resulting in reductions of 52% and 75%, respectively, in the area under the plasma concentration versus time curve and in plasma concentration. peak.
Administration of VIMOVO 30 minutes prior to food has only minimal or no effects on the amount and time of absorption of naproxen and has no significant effect on the rate or amount of esomeprazole absorption compared to administration in the fasted state (see paragraph 4.2).
Naproxen has a volume of distribution of 0.16 l / kg. At therapeutic levels, naproxen is more than 99% bound to albumin. The naproxen anion has been detected in the milk of lactating women at concentrations equivalent to approximately 1% of the maximum plasma naproxen concentration (see section 4.6). .
The apparent steady-state volume of distribution in healthy subjects is approximately 0.22 L / kg body weight. Esomeprazole has a plasma protein binding of 97%.
30% of naproxen is metabolised in the liver by the cytochrome P450 (CYP) system, mainly by CYP2C9, into 6-0-desmethyl naproxen. Neither the parent drug nor its metabolites induce metabolizing enzymes.Both naproxen and 6-0-desmethyl naproxen are further metabolised to their respective conjugated acylglucuronide metabolites.
Esomeprazole is completely metabolised by the CYP system. Most of the metabolism of esomeprazole depends on the CYP2C19 polymorph, which is responsible for the formation of the hydroxy and desmethyl metabolites of esomeprazole. The remainder depends on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the major plasma metabolite. The major metabolites of esomeprazole have no effect on gastric acid secretion.
After twice daily administration of VIMOVO, the mean elimination half-life of naproxen is approximately 9 hours and 15 hours following the morning and evening dose, respectively, with no change following repeated administration.
The clearance of naproxen is 0.13 ml / min / kg. Regardless of the dose, approximately 95% of any dose of naproxen is excreted in the urine, mainly as naproxen (faeces. In patients with renal insufficiency, metabolites may accumulate (see section 4.4).
After twice daily administration of VIMOVO, the mean elimination half-life of esomeprazole is approximately 1 hour following the morning and evening dose on the first day with a slightly longer elimination half-life at steady state (1.2-1 ,5 hours).
Total plasma clearance of esomeprazole is approximately 17 L / h after a single dose and approximately 9 L / h after repeated administration.
Almost 80% of an oral dose of esomeprazole is excreted as metabolites in urine, the rest in faeces. Less than 1% of the original drug is found in the urine.
Linearity / non-linearity
At doses of naproxen above 500 mg / day there is a less than proportional increase in plasma levels due to an increase in clearance caused by plasma protein binding saturation at higher doses (minimum mean Css 36.5, 49.2 and 56.4 mg / l with daily doses of naproxen of 500, 1,000 and 1,500 mg respectively).
The area under the plasma concentration-time curve of esomeprazole increases with repeated administration of VIMOVO. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time and dose dependence is in due to a reduction in first pass metabolism and systemic clearance possibly due to an "inhibition of the CYP2C19 enzyme by esomeprazole and / or its sulphone metabolite. An increase in esomeprazole absorption with repeated administration of VIMOVO has probably also contributed to time and dose dependence (see Absorption).
The pharmacokinetics of VIMOVO have not been determined in patients with renal insufficiency.
Naproxen: The pharmacokinetics of naproxen have not been determined in subjects with renal insufficiency.
Since naproxen, its metabolites and conjugates are primarily excreted by the kidneys, there is the potential for naproxen metabolites to accumulate in the presence of renal insufficiency. The elimination of naproxen is reduced in patients with severe renal insufficiency. The use of VIMOVO is contraindicated in patients with severe renal insufficiency (creatinine clearance
Esomeprazole: Studies with esomeprazole have not been conducted in patients with impaired renal function. Since the kidneys are responsible for the excretion of the metabolites of esomeprazole, but not for the elimination of the parent compound, an alteration of the metabolism of esomeprazole is not expected in patients with impaired renal function.
The pharmacokinetics of VIMOVO have not been determined in patients with impaired hepatic function.
Naproxen: The pharmacokinetics of naproxen have not been determined in subjects with hepatic insufficiency.
Chronic alcoholic liver disease and possibly other forms of cirrhosis also reduce the total plasma concentration of naproxen, but the plasma concentration of free naproxen is increased. The implication of this for the dosage of the naproxen component of VIMOVO is not known, 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 rate of drug metabolised is reduced in patients with severe hepatic impairment resulting in a doubling of the area under the plasma concentration-time curve for esomeprazole.
Patients with severe hepatic impairment should not take VIMOVO (see section 4.3).
There are no specific data on the pharmacokinetics of VIMOVO in patients over 65 years of age.
Naproxen: Some studies indicate that although the total plasma concentration of naproxen is unaltered, the free plasma fraction of naproxen is increased in the elderly, however the free fraction is
Esomeprazole: The metabolism of esomeprazole is not significantly changed in elderly subjects (aged 71 to 80 years).
Poor metabolisers CYP2C19
Esomeprazole: Approximately 3% of the population has a lack of CYP2C19 enzyme function; these individuals are referred to as poor metabolisers. In these individuals the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated administration of 40 mg daily doses of esomeprazole (once daily), the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects with CYP2C19 enzyme functionality (extensive metabolisers). Mean concentrations peak plasma levels was approximately 60% higher.
These results have no implications for the posology of VIMOVO.
Esomeprazole: After 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 differences were observed after repeated single dose administration. These results have no implication for the dosage of VIMOVO.
05.3 Preclinical safety data
No non-clinical data are available on the combination of active substances. There are no known interactions between naproxen and esomeprazole that may indicate new or adverse pharmacological, drug / toxicokinetic, toxicological, chemical / physical interaction or tolerability problems resulting from their combination.
Non-clinical data revealed no special hazard for humans based on conventional studies of genotoxicity, carcinogenic potential, embryo-fetal toxicity and fertility. The main findings at high doses in repeated oral dose toxicity studies in animals were gastrointestinal irritation and renal damage. , both attributable to the inhibition of prostaglandin synthesis. Oral administration of naproxen to female rats in the third trimester of pregnancy in peri- and postnatal studies resulted in difficult labor. This is a known effect for this category of drugs.
Preclinical studies ". Bridging". revealed no special hazard to humans based on conventional studies of repeated dose toxicity, genotoxicity and reproductive toxicity. Rat carcinogenicity studies with the racemic mixture demonstrated gastric ECL cell hyperplasia and carcinoids. These gastric effects in the rats are the result of high and prolonged hypergastrinaemia secondary to reduced gastric acid production and have been observed after long-term treatment in rats with gastric acid secretion inhibitors.
06.0 PHARMACEUTICAL INFORMATION
Core of the tablet
Silica, colloidal anhydrous
Glycerol monostearate 40-55
Iron oxide E172 (yellow)
Methacrylic acid-ethyl acrylate copolymer (1: 1)
Methyl parahydroxybenzoate E218 *
Propyl parahydroxybenzoate E216 *
Sodium lauryl sulfate
Titanium dioxide E171
Iron oxide E172 (black)
* These preservatives are present in the film coating mixture and are contained in the finished product at very low, non-functional levels.
06.3 Period of validity
06.4 Special precautions for storage
Do not store above 30 ° C.
Bottle: Store in the original package and keep the bottle tightly closed to protect from moisture.
Blisters: Store in the original package to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package
HDPE bottles containing silica gel desiccants with child resistant or non child resistant polypropylene closure (distributive packaging) with induction seal. The bag containing the desiccant must not be swallowed.
Pack sizes: 6, 20, 30, 60, 100, 180 or 500 modified release tablets.
Aluminum / aluminum blister.
Pack sizes: 10, 20, 30, 60 or 100 modified release tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions
07.0 MARKETING AUTHORIZATION HOLDER
Via F. Sforza
20080 Basiglio (MI)
08.0 MARKETING AUTHORIZATION NUMBER
Vimovo "500 mg / 20 mg modified release tablets"
6 Tablets In Hdpe Bottle - AIC: 040611016
20 Tablets In Hdpe Bottle - AIC 040611028
30 Tablets In Hdpe Bottle - AIC: 040611030
60 Tablets In Hdpe Bottle - AIC: 040611042
100 Tablets In Hdpe Bottle - AIC: 040611055
180 Tablets In Hdpe Bottle - AIC: 040611067
500 Tablets In Hdpe Bottle - AIC: 040611079
10 Tablets In Al / Al Blister - AIC: 040611081
20 Tablets In Al / Al Blister - AIC: 040611093
30 Tablets In Al / Al Blister - AIC: 040611105
60 Tablets In Al / Al Blister - AIC: 040611117
100 Tablets In Al / Al Blister - AIC: 040611129
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
10.0 DATE OF REVISION OF THE TEXT