Kinloft may be available in the countries listed below.
Sertraline hydrochloride (a derivative of Sertraline) is reported as an ingredient of Kinloft in the following countries:
International Drug Name Search
Generic Name: estradiol and levonorgestrel (topical patches) (ess tra DY ol and LEE vo nor JESS trell)
Brand Names: Climara Pro
Estradiol is a form of estrogen, a female hormone involved in the development and maintenance of the female reproductive system. Levonorgestrel is a form of progesterone, a female hormone important for regulating ovulation and menstruation.
Estradiol and levonorgestrel is used to treat menopause symptoms such as hot flashes, and to prevent osteoporosis (bone loss) in menopausal women. This medication will not prevent dementia, heart attack, heart disease, or stroke.
Estradiol and levonorgestrel may also be used for purposes other than those listed here.
To be sure this medication is helping your condition, you will need to have regular physical exams every 3 to 6 months. You may also need breast mammograms. It is important that you not miss any scheduled visits to your doctor. Call your doctor at any time if you have unusual vaginal bleeding.
a history of stroke, heart attack, or blood clots;
liver disease;
unusual vaginal bleeding; or
a history of breast, uterine, or hormone-related cancer.
Before using estradiol and levonorgestrel, tell your doctor if you have:
high blood pressure, angina, or heart disease;
asthma;
epilepsy;
migraines;
a thyroid disorder; or
endometriosis.
If you have any of the conditions listed above, you may not be able to use estradiol and levonorgestrel, or you may need a dosage adjustment or special tests during treatment.
You may need to stop using estradiol and levonorgestrel for a short time if you will have surgery or you become ill and must stay in bed for any length of time. Tell any doctor who treats you that you are using this medication.
Estradiol may increase your risk of developing endometrial hyperplasia, a condition that can lead to cancer of the uterus. Using levonorgestrel (a progestin) with estradiol can lower the risk of developing this condition.
Have yearly physical exams and examine your breasts for lumps on a monthly basis while using estradiol and levonorgestrel. It is important that you not miss any scheduled visits to your doctor. Call your doctor at any time if you have unusual vaginal bleeding.
Use the estradiol and levonorgestrel patches exactly as your doctor has prescribed them for you. Do not use more patches than recommended or use them for longer than your doctor has prescribed.
If you have been using another form of estrogen and progestin and are switching to estradiol and levonorgestrel skin patches, finish your current cycle of treatment first. If you are not already using an estrogen or progestin, you may begin using the skin patches at any time.
To use estradiol and levonorgestrel patches:
Apply each patch to a clean, dry, and smooth (fold free) area of skin on the lower stomach (below the belly button). Do not use the patch on your breasts or at your waistline, where tight-fitting clothing may interfere with its use. Do not apply to broken or irritated skin.
Open the pouch and take out the patch. Remove one side of the protective liner, trying not to touch the sticky part. Apply the patch and then remove the second side of the liner. Press the patch firmly in place with your hand for at least 10 seconds, making sure there is good contact, especially around the edges.
If a patch falls off, reapply it to another place on your lower abdomen. If it will not stick, apply a new patch.
The patch should be worn around-the-clock for one week. Replace the patch on the same day each week as directed by your doctor. Use only one patch at a time.
Choose a new place on your lower abdomen each time you apply a patch. Allow at least 1 week to pass before applying a patch to the same place.
After one week, remove the patch and fold it in half so that it sticks to itself. Used patches still contain active hormones and should be discarded out of the reach of children and pets.
Remove the patch carefully and slowly to avoid irritating your skin. Any adhesive remaining on the skin can be removed with baby oil.
To be sure this medication is helping your condition, you will need to have regular physical exams every 3 to 6 months. You may also need breast mammograms. It is important that you not miss any scheduled visits to your doctor. Call your doctor at any time if you have unusual vaginal bleeding.
If you use this medication to prevent osteoporosis, your doctor may also recommend weight-bearing exercise, calcium and vitamin D supplements, and dietary changes. Follow these directions carefully and ask your doctor before using any supplements.
Apply the next patch as soon as you remember. Continue to follow your regular schedule for changing the patch. Do not use extra patches to make up the missed dose.
Call your doctor at once if you have any of the following serious side effects:
signs of a blood clot (sharp chest pain, coughing up blood, shortness of breath, pain in your calf);
signs of a heart attack (crushing chest pain, left-arm numbness);
signs of a stroke (sudden severe headache, problems with vision or speech, weakness, numbness);
nausea, stomach pain, low fever, lost appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
new or changing breast lumps.
Other less serious side effects are more likely to occur, such as:
nausea and vomiting;
tender or swollen breasts;
swelling of the hands or feet;
darkened spots on the skin of your face;
contact lens discomfort;
vaginal irritation or discomfort;
headache, depressed mood;
a skin rash or reaction where the patch is worn; or
changes in your menstrual periods.
Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.
Usual Adult Dose for Postmenopausal Symptoms:
For the treatment of postmenopausal symptoms and/or the prevention of postmenopausal osteoporosis:
One (0.045 mg-0.015 mg/24 hr) patch applied weekly.
The patch should not be applied to, or near, the breasts. The application site should be smooth, clean, dry, fold-free, without damage or irritation, and be rotated with an interval of at least one week allowed to pass between applications to the same site.
If a patch dislodges, it may be reapplied to another area of the lower abdomen, or a new patch may be applied, in which case, the original treatment schedule resumes. However, only one patch should be worn at any given time during the weekly dosing interval.
Usual Adult Dose for Prevention of Osteoporosis:
For the treatment of postmenopausal symptoms and/or the prevention of postmenopausal osteoporosis:
One (0.045 mg-0.015 mg/24 hr) patch applied weekly.
The patch should not be applied to, or near, the breasts. The application site should be smooth, clean, dry, fold-free, without damage or irritation, and be rotated with an interval of at least one week allowed to pass between applications to the same site.
If a patch dislodges, it may be reapplied to another area of the lower abdomen, or a new patch may be applied, in which case, the original treatment schedule resumes. However, only one patch should be worn at any given time during the weekly dosing interval.
Before using estradiol and levonorgestrel, tell your doctor if you are taking an anticoagulant (blood thinner) such as warfarin (Coumadin). You may not be able to use estradiol and levonorgestrel, or you may require a dosage adjustment or special tests during treatment.
There may be other drugs that can affect estradiol and levonorgestrel. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.
See also: estradiol and levonorgestrel side effects (in more detail)
Rapime may be available in the countries listed below.
Cefepime Hydrochloride (a derivative of Cefepime) is reported as an ingredient of Rapime in the following countries:
International Drug Name Search
In the US, Panamax is a member of the drug class miscellaneous analgesics and is used to treat Fever, Muscle Pain, Pain and Sciatica.
Paracetamol is reported as an ingredient of Panamax in the following countries:
International Drug Name Search
Mobic 15 mg
Suppositories
(Meloxicam)
Please read this leaflet carefully. It contains a summary of the information available on your medicine. The information in the leaflet applies to MOBIC 15 mg Suppositories only. If after reading this you have any questions, ask your doctor or pharmacist.
The name of your medicine is MOBIC 15 mg Suppositories. Each suppository contains 15 mg meloxicam as the active ingredient.
The suppositories also contain the following inactive ingredients: hard fat and macrogolglycerolhydroxystearate.
MOBIC 15 mg Suppositories are available in cartons containing 12 suppositories.
MOBIC 15 mg Suppositories belong to a group of medicines called non-steroidal anti-inflammatory drugs which are used to reduce inflammation and pain in the joints and muscles.
The Marketing Authorisations for MOBIC 15 mg Suppositories in the U.K. and Republic of Ireland are held by:
and the suppositories are manufactured by:
In the U.K. and the Republic of Ireland the product is distributed by:
MOBIC 15 mg Suppositories are for the long-term treatment of rheumatoid arthritis and ankylosing spondylitis.
Your doctor may monitor your progress whilst on treatment.
Medicines such as MOBIC 15 mg Suppositories may be associated with a small increased risk of heart attack (“myocardial infarction”) or stroke. Any risk is more likely with high doses and prolonged treatment. Do not exceed the recommended dose or duration of treatment.
If you have heart problems, previous stroke or think that you might be at risk of these conditions (for example if you have high blood pressure, diabetes or high cholesterol or are a smoker) you should discuss your treatment with your doctor or pharmacist.
This product should not be used during pregnancy. If you are planning to become pregnant, if you think or know you are pregnant you should talk to your doctor for advice.
This product should not be given to breast feeding mothers.
Visual disturbances, drowsiness, vertigo (dizziness) may occur with this product. If affected do not drive or operate machinery.
As MOBIC 15mg Suppositories may affect or be affected by other medicines, please tell your doctor or pharmacist if you are taking, or have recently taken any other medicines, even those not prescribed.
In particular please tell your doctor or pharmacist if you are taking/have taken any of the following:
If in doubt, ask your doctor or pharmacist.
Follow your doctor’s instructions about when and how to use your medicine and always read the label. If you are unsure, ask your doctor or pharmacist.
The usual recommended doses are given below. As there are two strengths of suppositories (7.5 mg and 15 mg) your doctor will ensure that you are given the right strength.
Rheumatoid arthritis: 15 mg (one 15 mg suppository) once a day. This may be reduced to 7.5 mg (one 7.5 mg suppository) once a day.
Ankylosing spondylitis: 15 mg (one 15 mg suppository) once a day. This may be reduced to 7.5 mg (one 7.5 mg suppository) once a day.
The suppositories are for rectal use and should be used as follows. They should not be swallowed.
If you feel uncomfortable and feel that the suppository must come out immediately, it has probably not been inserted high enough.
Do not exceed the recommended maximum dose of 15 mg a day.
If any of the statements listed under the heading ‘Take special care when taking this medicine if’ apply to you, your doctor may restrict your dose to 7.5 mg (one suppository) once a day.
MOBIC 15 mg Suppositories should not be given to children under 15 years of age.
If you feel that the effect of MOBIC 15 mg Suppositories is too strong or too weak, talk to your doctor or pharmacist.
If you take more MOBIC 15 mg Suppositories than you should, talk to your doctor or pharmacist immediately.
If you forget to take MOBIC 15 mg Suppositories do not take a double dose (two suppositories) to make up for the missed dose.
If after several days you do not feel any improvement in your condition then you should talk to your doctor or pharmacist.
All medicines can cause side effects. Medicines such as MOBIC 15 mg Suppositories may be associated with a small increased risk of heart attack (“myocardial infarction”) or stroke.
The side effects described below have been experienced by people taking MOBIC and they are listed as either common, uncommon or rare.
If a side effect is listed as
Common: indigestion, feeling sick or being sick, abdominal pain, constipation, flatulence, diarrhoea
Uncommon: gastrointestinal bleeding (causing offensive, tar-coloured stools), ulcers of the stomach or intestines, inflammation or soreness of the mouth or the gullet
Rare: gastrointestinal perforation (a hole in the wall of the bowel), inflammation or soreness of the stomach or the colon
Ulcers of the stomach or intestines, gastrointestinal bleeding and gastrointestinal perforation can occur at any time and can sometimes be severe, especially in the elderly and very rarely have been fatal.
If you have a history of gastrointestinal symptoms whilst taking anti-inflammatory drugs, your doctor may monitor your progress whilst on treatment.
Common: itching, rash
Uncommon: urticaria (nettle rash)
Rare: severe blistering of the skin or peeling, swelling around the eyes, lips and face, rashes caused by exposure to sunlight
Common: lightheadedness, headache
Uncommon: vertigo (dizziness), tinnitus (noises in the ear), drowsiness
Rare: Confusion, mood disorders, insomnia (inability to sleep), nightmares
If affected by any of these side effects do not drive or operate machinery.
Rare: visual disturbances, for example blurred vision
If affected by visual disturbances do not drive or operate machinery.
Common: swelling caused by fluid retention, including swollen ankles/legs
Uncommon: palpitations, increase in blood pressure, hot flushes
Common: anaemia
Uncommon: abnormality of white blood cell or platelet numbers
Rare: severe allergic reactions which may include fainting, shortness of breath and skin reactions
Rare: Asthma attacks (seen in people who are allergic to aspirin or other non-steroidal anti-inflammatory drugs)
Uncommon: changes in tests of liver function
Rare: inflammation of the liver (hepatitis)
Uncommon: salt and water retention, increased potassium levels in the blood, changes in tests of kidney function
Rare: kidney failure
Irritation of the rectum - especially if suppositories are used for long periods, frequently or at high doses.
The following side effects have been seen with other medicines similar to MOBIC but have not yet been reported by patients taking MOBIC: Changes to the kidney structure resulting in kidney failure: isolated cases kidney inflammation, death of some of the cells within the kidney, proteinuria (protein in the urine).
If you experience any of these side effects and they persist or become troublesome, consult your doctor.
If you experience any other side effects not mentioned above, consult your doctor or pharmacist.
The suppositories should not be used after the expiry date which is printed on the packaging.
Store below 30°C.
Keep this medicine out of the sight and reach of children.
This leaflet was revised in April 2007.
Remember this medicine is for you.
Only a doctor can prescribe it for you. Never give it to others as it may harm them even if their symptoms are the same as yours.
© Boehringer Ingelheim Limited 2007
437855/GB/10
MINTEC* 0.2 ml GASTRO-RESISTANT CAPSULES
Peppermint Oil BP
This medicine is available without prescription. However, you still need to take Mintec carefully to get the best results from it.
Mintec capsules contain a naturally occurring oil extracted from the peppermint plant which is used to relieve the symptoms of irritable bowel syndrome (IBS).
Mintec relaxes spasm in the muscle of the bowel wall and helps restore normal bowel contractions. This helps to decrease the trapping of air and other bowel contents and relieves abdominal bloating, wind, discomfort and pain.
If any of the above applies to you, please check with your pharmacist before taking Mintec.
If you suffer from pre-existing heartburn, the symptoms may worsen.
Mintec is not known to interact with any other medicinal products. Please ask your doctor or pharmacist if you are unsure.
Take Mintec preferably before food, with a little liquid. Do not take Mintec immediately after food.
Skin rash, slow heartbeat, or trembling and unsteadiness are rare allergic reactions which may occur when Mintec is taken with alcohol (see Section 4 ‘Possible side effects’).
Ask your doctor or pharmacist for advice if you
before taking Mintec.
Swallow the capsules whole with a little liquid. Do not chew or break the capsules.
If you experience new symptoms, worsening of your condition or notice no improvement after two weeks of treatment, please see your doctor.
If you accidentally take more Mintec than you should, contact your doctor or emergency department as soon as possible. Take the packet and any remaining capsules with you.
If you forget to take a dose, leave out that dose completely. Take your next dose when it is due. Do not take a double dose to make up for a forgotten dose.
Like all medicines, Mintec can cause side effects, although not everybody gets them.
Heartburn may occur. If you develop this symptom, stop taking the capsules and see your doctor.
Rarely, allergic reactions to Mintec have been reported, including:
These may also occur if Mintec is taken with alcohol.
If any of these side effects gets serious, or if you notice any side effect(s) not listed in this leaflet, please talk to your doctor or pharmacist.
Keep out of the reach and sight of children.
Do not use Mintec after the expiry date (‘EXP’) which is printed on the pack.
Store Mintec at room temperature (not above 25°C) in the original package to protect from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
Each capsule contains 0.2 ml naturally occurring peppermint oil from the peppermint plant as the active ingredient.
The capsule shell contains gelatin, glycerol, titanium dioxide and chlorophyll KK.
The capsule coating contains hydroxypropylmethyl cellulose phthalate and dibutyl phthalate.
The soft capsules are coloured half green and half ivory.
The capsules are contained in blister strips. Each pack contains 84 capsules.
Marketing Authorisation Holder
Manufacturer
This leaflet was last updated in January 2008.
* Trade Mark Monmouth is a member of the Shire Group of Companies
Relafen (nabumetone) is a naphthylalkanone designated chemically as 4-(6-methoxy-2-naphthalenyl)-2-butanone. It has the following structure:
[
Nabumetone is a white to off-white crystalline substance with a molecular weight of 228.3. It is nonacidic and practically insoluble in water, but soluble in alcohol and most organic solvents. It has an n-octanol:phosphate buffer partition coefficient of 2400 at pH 7.4.
Each oval-shaped, film-coated tablet contains 500 mg or 750 mg of nabumetone. Inactive ingredients consist of hypromellose, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium lauryl sulfate, sodium starch glycolate, and titanium dioxide. The 750-mg tablets also contain iron oxides.
Relafen is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic properties in pharmacologic studies. As with other non-steroidal anti-inflammatory agents, its mode of action is not known; however, the ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect.
The parent compound is a prodrug, which undergoes hepatic biotransformation to the active component, 6-methoxy-2-naphthylacetic acid (6MNA), that is a potent inhibitor of prostaglandin synthesis.
It is acidic and has an n-octanol:phosphate buffer partition coefficient of 0.5 at pH 7.4.
After oral administration, approximately 80% of a radiolabeled dose of nabumetone is found in the urine, indicating that nabumetone is well absorbed from the gastrointestinal tract. Nabumetone itself is not detected in the plasma because, after absorption, it undergoes rapid biotransformation to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA). Approximately 35% of a 1,000-mg oral dose of nabumetone is converted to 6MNA and 50% is converted into unidentified metabolites which are subsequently excreted in the urine. Following oral administration of RELAFEN, 6MNA exhibits pharmacokinetic characteristics that generally follow a one-compartment model with first order input and first order elimination.
6MNA is more than 99% bound to plasma proteins. The free fraction is dependent on total concentration of 6MNA and is proportional to dose over the range of 1,000 mg to 2,000 mg. It is 0.2% to 0.3% at concentrations typically achieved following administration of 1,000 mg of Relafen and is approximately 0.6% to 0.8% of the total concentrations at steady state following daily administration of 2,000 mg.
Steady-state plasma concentrations of 6MNA are slightly lower than predicted from single-dose data. This may result from the higher fraction of unbound 6MNA which undergoes greater hepatic clearance.
Coadministration of food increases the rate of absorption and subsequent appearance of 6MNA in the plasma but does not affect the extent of conversion of nabumetone into 6MNA. Peak plasma concentrations of 6MNA are increased by approximately one third.
Coadministration with an aluminum-containing antacid had no significant effect on the bioavailability of 6MNA.
Abbreviation (units) | Young Adults Mean ± SD1,000 mg n = 31 | Young Adults Mean ± SD 2,000 mg n = 12 | Elderly Mean ± SD 1,000 mg n = 27 |
Tmax (hr) | 3.0 (1.0 to 12.0) | 2.5 (1.0 to 8.0) | 4.0 (1.0 to 10.0) |
t½ (hr) | 22.5 ± 3.7 | 26.2 ± 3.7 | 29.8 ± 8.1 |
CLss/F (mL/min) | 26.1 ± 17.3 | 21.0 ± 4.0 | 18.6 ± 13.4 |
Vdss/F (L) | 55.4 ± 26.4 | 53.4 ± 11.3 | 50.2 ± 25.3 |
The simulated curves in the graph below illustrate the range of active metabolite plasma concentrations that would be expected from 95% of patients following 1,000-mg to 2,000-mg doses to steady state. The cross-hatched area represents the expected overlap in plasma concentrations due to intersubject variation following oral administration of 1,000 mg to 2,000 mg of RELAFEN.
6MNA undergoes biotransformation in the liver, producing inactive metabolites that are eliminated as both free metabolites and conjugates. None of the known metabolites of 6MNA has been detected in plasma. Preliminary in vivo and in vitro studies suggest that unlike other NSAIDs, there is no evidence of enterohepatic recirculation of the active metabolite. Approximately 75% of a radiolabeled dose was recovered in urine in 48 hours. Approximately 80% was recovered in 168 hours. A further 9% appeared in the feces. In the first 48 hours, metabolites consisted of:
−nabumetone, unchanged | not detectable |
−6-methoxy-2-naphthylacetic acid | <1% |
(6MNA), unchanged | |
−6MNA, conjugated | 11% |
−6-hydroxy-2-naphthylacetic acid | 5% |
(6HNA), unchanged | |
−6HNA, conjugated | 7% |
−4-(6-hydroxy-2-naphthyl)-butan-2-ol, | 9% |
Conjugated | |
−O-desmethyl-nabumetone, conjugated | 7% |
−unidentified minor metabolites | 34% |
Total % Dose: | 73% |
Following oral administration of dosages of 1,000 mg to 2,000 mg to steady state, the mean plasma clearance of 6MNA is 20 to 30 mL/min and the elimination half-life is approximately 24 hours.
Steady-state plasma concentrations in elderly patients were generally higher than in young healthy subjects (see Table 1 for summary of pharmacokinetic parameters).
In moderate renal insufficiency patients (creatinine clearance 30 to 49 mL/min), the terminal half-life of 6MNA was increased by approximately 50% (39.2 ± 7.8 hrs, N=12) compared to the normal subjects (26.9 ± 3.3 hrs, N=13), and there was a 50% increase in the plasma levels of unbound 6MNA.
Additionally, the renal excretion of 6MNA in the moderate renal impaired patients decreased on average by 33% compared to that in the normal patients. A similar increase in the mean terminal half-life of 6MNA was seen in a small study of patients with severe renal dysfunction (creatinine clearance <30 mL/min). In patients undergoing hemodialysis, steady-state plasma concentrations of the active metabolite 6MNA were similar to those observed in healthy subjects. Due to extensive protein binding, 6MNA is not dialyzable
Dosage adjustment of Relafen generally is not necessary in patients with mild renal insufficiency (≥50 mL/min). Caution should be used in prescribing Relafen to patients with moderate or severe renal insufficiency. The maximum starting doses of Relafen in patients with moderate or severe renal insufficiency should not exceed 750 mg or 500 mg, respectively once daily. Following careful monitoring of renal function in patients with moderate or severe renal insufficiency, daily doses may be increased to a maximum of 1,500 mg and 1,000 mg, respectively (see WARNINGS: Renal Effects).
Data in patients with severe hepatic impairment are limited. Biotransformation of nabumetone to 6MNA and the further metabolism of 6MNA to inactive metabolites is dependent on hepatic function and could be reduced in patients with severe hepatic impairment (history of or biopsy-proven cirrhosis).
Relafen was compared to aspirin in inducing gastrointestinal blood loss. Food intake was not monitored. Studies utilizing 51Cr-tagged red blood cells in healthy males showed no difference in fecal blood loss after 3 or 4 weeks’ administration of 1,000 mg or 2,000 mg of Relafen daily when compared to either placebo-treated or nontreated subjects. In contrast, aspirin 3,600 mg daily produced an increase in fecal blood loss when compared to subjects who received RELAFEN, placebo, or no treatment. The clinical relevance of the data is unknown.
The following endoscopy trials entered patients who had been previously treated with NSAIDs. These patients had varying baseline scores and different courses of treatment. The trials were not designed to correlate symptoms and endoscopy scores. The clinical relevance of these endoscopy trials, i.e., either G.I. symptoms or serious G.I. events, is not known.
Ten endoscopy studies were conducted in 488 patients who had baseline and post-treatment endoscopy. In 5 clinical trials that compared a total of 194 patients on 1,000 mg of Relafen daily or naproxen 250 mg or 500 mg twice daily for 3 to 12 weeks, treatment with RELAFEN resulted in fewer patients with endoscopically detected lesions (>3 mm). In 2 trials a total of 101 patients administered 1,000 mg or 2,000 mg of Relafen daily or piroxicam 10 mg to 20 mg for 7 to 10 days, there were fewer patients treated with Relafen with endoscopically detected lesions. In 3 trials of a total of 47 patients on 1,000 mg of Relafen daily or indomethacin 100 mg to 150 mg daily for 3 to 4 weeks, the endoscopy scores were higher with indomethacin. Another 12-week trial in a total of 171 patients compared the results of treatment with 1,000 mg of Relafen daily to ibuprofen 2,400 mg/day and ibuprofen 2,400 mg/day plus misoprostol 800 mcg/day. The results showed that patients treated with Relafen had a lower number of endoscopically detected lesions (>5 mm) than patients treated with ibuprofen alone but comparable to the combination of ibuprofen plus misoprostol. The results did not correlate with abdominal pain.
In 1-week, repeat-dose studies in healthy volunteers, 1,000 mg of Relafen daily had little effect on collagen-induced platelet aggregation and no effect on bleeding time. In comparison, naproxen 500 mg daily suppressed collagen-induced platelet aggregation and significantly increased bleeding time.
The use of Relafen in relieving the signs and symptoms of osteoarthritis (OA) was assessed in double-blind, controlled trials in which 1,047 patients were treated for 6 weeks to 6 months. In these trials, Relafen in a dose of 1,000 mg/day administered at night was comparable to naproxen 500 mg/day and to aspirin 3,600 mg/day.
The use of Relafen in relieving the signs and symptoms of rheumatoid arthritis (RA) was assessed in double-blind, randomized, controlled trials in which 770 patients were treated for 3 weeks to 6 months. RELAFEN, in a dose of 1,000 mg/day administered at night, was comparable to naproxen 500 mg/day and to aspirin 3,600 mg/day.
In controlled clinical trials of rheumatoid arthritis patients, Relafen has been used in combination with gold, d-penicillamine, and corticosteroids.
In clinical trials with osteoarthritis and rheumatoid arthritis patients, most patients responded to Relafen in doses of 1,000 mg/day administered nightly; total daily dosages up to 2,000 mg were used. In open-labeled studies, 1,490 patients were permitted dosage increases and were followed for approximately 1 year (mode). Twenty percent of patients (n = 294) were withdrawn for lack of effectiveness during the first year of these open-labeled studies. The following table provides patient-exposure to doses used in the US clinical trials:
Relafen in Osteoarthritis and Rheumatoid Arthritis
Dose of RELAFEN | Number of Patients | Mean/Mode Duration of Treatment (yr) | ||
OA | RA | OA | RA | |
500 mg | 17 | 6 | 0.4/− | 0.2/− |
1,000 mg | 917 | 701 | 1.2/1 | 1.4/1 |
1,500 mg | 645 | 224 | 2.3/1 | 1.7/1 |
2,000 mg | 15 | 100 | 0.6/1 | 1.3/1 |
As with other NSAIDs, the lowest dose should be sought for each patient. Patients weighing under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients’ requirements.
Carefully consider the potential benefits and risks of Relafen and other treatment options before deciding to use RELAFEN. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
RELAFEN is indicated for relief of signs and symptoms of osteoarthritis and rheumatoid arthritis.
Relafen is contraindicated in patients with known hypersensitivity to nabumetone or its excipients.
RELAFEN should not be given to 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 (see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS, General, Preexisting Asthma).
RELAFEN is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects―Risk of Ulceration, Bleeding, and Perforation).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).
NSAIDs, including RELAFEN, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including RELAFEN, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAIDtreatment and throughout the course of therapy.
Fluid retention and edema have been observed in some patients taking NSAIDs. Relafen should be used with caution in patients with fluid retention or heart failure.
NSAIDs, including RELAFEN, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only 1 in 5 patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for 1 year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
In controlled clinical trials involving 1,677 patients treated with Relafen (1,140 followed for 1 year and 927 for 2 years), the cumulative incidence of peptic ulcers was 0.3% (95% CI; 0%, 0.6%) at 3 to 6 months, 0.5% (95% CI; 0.1%, 0.9%) at 1 year and 0.8% (95% CI; 0.3%, 1.3%) at 2 years. In patients with active peptic ulcer, physicians must weigh the benefits of therapy with Relafen against possible hazards, institute an appropriate ulcer treatment regimen and monitor the patients’ progress carefully.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
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 an NSAID results in a dose-dependent decrease in prostaglandin synthesis and, secondarily, in a reduction of renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of Relafen in patients with advanced renal disease. Therefore, treatment with Relafen is not recommended in these patients with advanced renal disease. If Relafen therapy must be initiated, close monitoring of the patient’s renal function is advisable.
Because nabumetone undergoes extensive hepatic metabolism, no adjustment of the dosage of Relafen is generally necessary in patients with mild renal insufficiency; however, as with all NSAIDs, patients with impaired renal function should be monitored more closely than patients with normal renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Renal Insufficiency ). In subjects with moderate renal impairment (creatinine clearance 30 to 49 mL/min), there is a 50% increase in unbound plasma 6MNA and dose adjustment may be warranted. The oxidized and conjugated metabolites of 6MNA are eliminated primarily by the kidneys.
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to RELAFEN. Relafen should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, General, Preexisting Asthma ). Emergency help should be sought in cases where an anaphylactoid reaction occurs.
NSAIDs, including RELAFEN, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
In late pregnancy, as with other NSAIDs, Relafen should be avoided because it may cause premature closure of the ductus arteriosus.
Relafen cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of Relafen in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Borderline elevations of 1 or more liver function tests may occur in up to 15% of patients taking NSAIDs including RELAFEN. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately 3 or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, 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. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with RELAFEN. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), RELAFEN should be discontinued.
Anemia is sometimes seen in patients receiving NSAIDS, including RELAFEN. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including RELAFEN, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Relafen who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored (see CLINICAL PHARMACOLOGY, Special Studies, Other ).
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Relafen should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Based on ultraviolet (U.V.) light photosensitivity testing, Relafen may be associated with more reactions to sun exposure than might be expected based on skin tanning types.
Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
Because serious G.I. tract ulceration and bleeding can occur without warning symptoms, physicians should monitor for signs and symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Relafen should be discontinued.
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
When RELAFEN is administered with aspirin, its protein binding is reduced, although the clearance of free Relafen is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of nabumetone and aspirin is not generally recommended because of the potential of increased adverse effects.
Clinical studies, as well as post marketing observations, have shown that Relafen 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 (see PRECAUTIONS, Renal Effects), as well as to assure diuretic efficacy.
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. 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.
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
In vitro studies have shown that, because of its affinity for protein, 6MNA may displace other protein-bound drugs from their binding site. Caution should be exercised when administering RELAFEN with warfarin since interactions have been seen with other NSAIDs.
Concomitant administration of an aluminum-containing antacid had no significant effect on the bioavailability of 6MNA. When administered with food or milk, there is more rapid absorption; however, the total amount of 6MNA in the plasma is unchanged (see CLINICAL PHARMACOLOGY, Pharmacokinetics).
In 2-year studies conducted in mice and rats, nabumetone had no statistically significant tumorigenic effect. Nabumetone did not show mutagenic potential in the Ames test and mouse micronucleus test in vivo; however, nabumetone- and 6MNA-treated lymphocytes in culture showed chromosomal aberrations at 80 mcg/mL and higher concentrations (equal to the average human exposure to Relafen at the maximum recommended dose).
Nabumetone did not impair fertility of male or female rats treated orally at doses of 320 mg/kg/day (1,888 mg/m2) before mating.
Pregnancy Category C. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate, well-controlled studies in pregnant women. Relafen should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Relafen on labor and delivery in pregnant women are unknown.
It is not known whether this drug is excreted in human milk, however 6MNA is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from RELAFEN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established.
As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). Of the 1,677 patients in US clinical studies who were treated with RELAFEN, 411 patients (24%) were 65 years or older; 22 patients (1%) were 75 years or older. No overall differences in efficacy or safety were observed between these older patients and younger ones. Similar results were observed in a 1-year, non-US postmarketing surveillance study of 10,800 patients treated with RELAFEN, of whom 4,577 patients (42%) were 65 years or older.
Adverse reaction information was derived from blinded-controlled and open-labelled clinical trials and from worldwide marketing experience. In the description below, rates of the more common events (greater than 1%) and many of the less common events (less than 1%) represent results of US clinical studies.
Of the 1,677 patients who received Relafen during US clinical trials, 1,524 were treated for at least 1 month, 1,327 for at least 3 months, 929 for at least a year, and 750 for at least 2 years. More than 300 patients have been treated for 5 years or longer.
The most frequently reported adverse reactions were related to the gastrointestinal tract and included diarrhea, dyspepsia, and abdominal pain.
Incidence≥1%—Probably Causally Related
Gastrointestinal: Diarrhea (14%), dyspepsia (13%), abdominal pain (12%), constipation*, flatulence*, nausea*, positive stool guaiac*, dry mouth, gastritis, stomatitis, vomiting. |
Central Nervous System: Dizziness*, headache*, fatigue, increased sweating, insomnia, nervousness, somnolence. |
Dermatologic: Pruritus*, rash*. |
Special Senses: Tinnitus*. |
Miscellaneous: Edema*. |
*Incidence of reported reaction between 3% and 9%. Reactions occurring in 1% to 3% of the patients are unmarked.
Incidence <1%—Probably Causally Related†
Gastrointestinal: Anorexia, jaundice, duodenal ulcer, dysphagia, gastric ulcer, gastroenteritis, gastrointestinal bleeding, increased appetite, liver function abnormalities, melena, hepatic failure. |
Central Nervous System: Asthenia, agitation, anxiety, confusion, depression, malaise, paresthesia, tremor, vertigo. |
Dermatologic: Bullous eruptions, photosensitivity, urticaria, pseudoporphyria cutanea tarda, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome. |
Cardiovascular: Vasculitis. |
Metabolic: Weight gain. |
Respiratory: Dyspnea, eosinophilic pneumonia, hypersensitivity pneumonitis, idiopathic interstitial pneumonitis. |
Genitourinary: Albuminuria, azotemia, hyperuricemia, interstitial nephritis, nephrotic syndrome, vaginal bleeding, renal failure. |
Special Senses: Abnormal vision. |
Hematologic/Lymphatic:Thrombocytopenia. |
Hypersensitivity: Anaphylactoid reaction, anaphylaxis, angioneurotic edema. |
†Adverse reactions reported only in worldwide postmarketing experience or in the literature, not seen in clinical trials, are considered rarer and are italicized.
Incidence <1%—Causal Relationship Unknown
Gastrointestinal: Bilirubinuria, duodenitis, eructation, gallstones, gingivitis, glossitis, pancreatitis, rectal bleeding. |
Central Nervous System: Nightmares. |
Dermatologic: Acne, alopecia. |
Cardiovascular: Angina, arrhythmia, hypertension, myocardial infarction, palpitations, syncope, thrombophlebitis. |
Respiratory: Asthma, cough. |
Genitourinary: Dysuria, hematuria, impotence, renal stones. |
Special Senses: Taste disorder. |
Body as a Whole: Fever, chills. |
Hematologic/Lymphatic: Anemia, leukopenia, granulocytopenia. |
Metabolic/Nutritional: Hyperglycemia, hypokalemia, weight loss. |
Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. 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.
Patients should be managed by symptomatic and supportive care following a NSAIDs overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 grams 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 (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
There have been overdoses of up to 25 grams of Relafen reported with no long-term sequelae following standard emergency treatment (i.e., activated charcoal, gastric lavage, IV H2-blockers, etc.).
Carefully consider the potential benefits and risks of RELAFEN and other treatment options before deciding to use RELAFEN. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with RELAFEN, the dose and frequency should be adjusted to suit an individual patient’s needs.
The recommended starting dose is 1,000 mg taken as a single dose with or without food. Some patients may obtain more symptomatic relief from 1,500 mg to 2,000 mg per day. Relafen can be given in either a single or twice-daily dose. Dosages greater than 2,000 mg per day have not been studied. The lowest effective dose should be used for chronic treatment (see WARNINGS, Renal Effects). Patients weighing under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients’ requirements.
Oval-shaped, film-coated: 500 mg−white, imprinted with the product name Relafen and 500, in bottles of 100. 750 mg−beige, imprinted with the product name Relafen and 750, in bottles of 100.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) in well-closed container; dispense in light-resistant container.
500 mg 100’s: NDC 0029-4851-20
750 mg 100’s: NDC 0029-4852-20
(see the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:
NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG)”.
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment.
Ulcers and bleeding:
The chance of a person getting an ulcer or bleeding increases with:
NSAID medicines should only be used:
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
Tell your healthcare provider:
