Meloxicam
- Generic Name: meloxicam
- Brand Name: Meloxicam Tablets
PATIENT INFORMATION
Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(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:
- with longer use of NSAID medicines
- in people who have heart disease
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:
- Can happen without warning symptoms
- May cause death
The chance of a person getting an ulcer or bleeding increases with:
- taking medicines called “corticosteroids” and “anticoagulants”
- longer use
- smoking
- drinking alcohol
- older age
- having poor health
NSAID medicines should only be used:
- exactly as prescribed
- at the lowest dose possible for your treatment
- for the shortest time needed
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:
- different types of arthritis
- menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
- if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
- for pain right before or after heart bypass surgery
Tell your healthcare provider:
- about all of your medical conditions
- about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist
- if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy
- if you are breastfeeding. Talk to your doctor
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
- heart attack
- stroke
- high blood pressure
- heart failure from body swelling (fluid retention)
- kidney problems including kidney failure
- bleeding and ulcers in the stomach and intestine
- low red blood cells (anemia)
- life-threatening skin reactions
- life-threatening allergic reactions
- liver problems including liver failure
- asthma attacks in people who have asthma
Other side effects include:
- stomach pain
- constipation
- diarrhea
- gas
- heartburn
- nausea
- vomiting
- dizziness
Get emergency help right away if you have any of the following symptoms :
- shortness of breath or trouble breathing
- chest pain
- weakness in one part or side of your body
- slurred speech
- swelling of the face or throat
Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms :
-
- nausea
- more tired or weaker than usual
- itching
- your skin or eyes look yellow
- stomach pain
- flu-like symptoms
- vomit blood
- there is blood in your bowel movement or it is black and sticky like tar
- unusual weight gain
- skin rash or blisters with fever
- swelling of the arms and legs, hands and feet
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):
- Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
- Some of these NSAID medicines are sold in lower doses without a prescription (over-thecounter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
| Generic Name | Product Trademark(s) |
| Celecoxib | Celebrex |
| Diclofenac | Cataflam, Voltaren, Arthrotec (combined with misoprostol) |
| Diflunisal | Dolobid |
| Etodolac | Lodine, Lodine XL |
| Fenoprofen | Nalfon, Nalfon 200 |
| Flurbiprofen | Ansaid |
| Ibuprofen | Motrin, Tab- Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined with oxycodone) |
| Indomethacin | Indocin, Indocin SR, Indo-Lemnun, Indoimethegan |
| Ketoprofen | Oruvail |
| Ketorolac | Toradol |
| Mefenamic Acid | Ponstel |
| Meloxicam | Mobic |
| Nabumetone | Relafen |
| Naproxen | Naprosyn, Anaprox, Anaprox DS, ECNaprosyn, Naprelan, Naprapac (copackaged with lansoprazole) |
| Oxaprozin | Daypro |
| Piroxicam | Feldene |
| Sulindac | Clinoril |
| Tolmelin | Tolectin, Tolectin DS, Tolectin 600 |
| * Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually use for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke. | |
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Description
Meloxicam, an oxicam derivative, is a member of the enolic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each light yellow colored tablet contains meloxicam 7.5 mg and light yellow colored tablet contains meloxicam 15 mg for oral administration. It is chemically designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2-H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C14H13N3O4S2 and it has the following structural formula.
Meloxicam
 |
Meloxicam is a pastel yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P)app= 0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2.
Meloxicam is available as a tablet for oral administration containing 7.5 mg or 15 mg meloxicam.
The inactive ingredients in meloxicam tablets, USP include colloidal silicon dioxide, crospovidone, Iron oxide (Ferric Oxide) (in 15 mg tablets only) lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium citrate dihydrate.
Indications
Meloxicam capsules are indicated for management of osteoarthritis pain.
Dosage And Administration
Dosage
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNINGS AND PRECAUTIONS].
For management of osteoarthritis pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of meloxicam capsules is 10 mg.
In patients on hemodialysis, the maximum daily dosage is 5 mg [see WARNINGS AND PRECAUTIONS, Use In Specific Populations, CLINICAL PHARMACOLOGY]
Non-Interchangeability With Other Formulations Of Meloxicam
Meloxicam capsules have not shown equivalent systemic exposure to other formulations of oral meloxicam. Therefore, meloxicam capsules are not interchangeable with other formulations of oral meloxicam even if the total milligram strength is the same. Do not substitute similar dose strengths of other meloxicam products [see CLINICAL PHARMACOLOGY].
How Supplied
Dosage Forms And Strengths
Meloxicam Capsules: 5 mg – Size ‘4’ Hard Gelatin Capsules having yellow opaque cap and yellow opaque body, imprinted with “LU” on cap and “M76” on body in black ink containing light yellow to yellow colored granules.
Meloxicam Capsules: 10 mg – Size ‘3’ Hard Gelatin Capsules having green opaque cap and green opaque body, imprinted with “LU” on cap and “M78” on body in black ink containing light yellow to yellow colored granules.
Storage And Handling
Meloxicam capsules are supplied as:
5 mg – yellow opaque cap and yellow opaque body (imprinted “M76” on the body and “LU” on the cap in black ink)
NDC (68180-188-06), Bottles of 30 capsules
NDC (68180-188-09), Bottles of 90 capsules
NDC (68180-188-02), Bottles of 500 capsules
10 mg – green opaque cap and green opaque body (imprinted “M78” on the body and “LU” on the cap in black ink)
NDC (68180-189-06), Bottles of 30 capsules
NDC (68180-189-09), Bottles of 90 capsules
NDC (68180-189-02), Bottles of 500 capsules
Storage
Store at 25 °C (77 °F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
Store in the original container and keep the bottle tightly closed to protect from moisture. Dispense in a tight container if package is subdivided.
Manufactured for: Lupin Pharmaceuticals, Inc., Baltimore, Maryland 21202. Manufactured by: Lupin Limited, Aurangabad 431 210. Revised: Jul 2021
Side Effects
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Cardiovascular Thrombotic Events [see WARNINGS AND PRECAUTIONS]
- GI Bleeding, Ulceration and Perforation [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Heart Failure and Edema [see WARNINGS AND PRECAUTIONS]
- Renal Toxicity and Hyperkalemia [see WARNINGS AND PRECAUTIONS]
- Anaphylactic Reactions [see WARNINGS AND PRECAUTIONS]
- Serious Skin Reactions [see WARNINGS AND PRECAUTIONS]
- Hematologic Toxicity [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions In Patients With Osteoarthritis Pain
Eight hundred sixty-eight (868) patients with osteoarthritis pain, ranging in age from 40 to 87 years, were enrolled in two Phase 3 clinical trials and received meloxicam capsules 5 mg or 10 mg once daily. Fifty percent (50%) of patients were aged 61 years or older.
Two hundred sixty-nine (269) patients received meloxicam capsules 5 mg or 10 mg once daily in the 12-week, double-blind, placebo-controlled, clinical trial of osteoarthritis pain of the knee or hip. The most frequent adverse reactions in this study are summarized in Table 1.
Table 1 : Summary of Adverse Reactions (≥2%) – 12-Week Phase 3 Study in Patients With Osteoarthritis Pain
| Adverse Reactions | Meloxicam Capsules 5 mg or 10 mg N=269 |
Placebo N=133 |
| Diarrhea | 3% | 1% |
| Nausea | 2% | 0 |
| Abdominal Discomfort | 2% | 0 |
Six hundred (600) patients received meloxicam capsules 10 mg once daily in a 52-week, open-label, clinical trial in osteoarthritis pain of the knee or hip. Of these, 390 (65%) patients completed the trial. The most frequent adverse reactions in this study are summarized in Table 2.
Table 2 : Summary of Adverse Reactions (≥2%) – 52-Week Open-Label Study in Patients With Osteoarthritis Pain
| Adverse Reactions | Meloxicam Capsules 10 mg N=600 |
| Arthralgia | 6% |
| Urinary Tract Infection | 6% |
| Osteoarthritis | 5% |
| Hypertension | 4% |
| Diarrhea | 4% |
| Headache | 4% |
| Upper Respiratory Tract Infection | 4% |
| Back Pain | 4% |
| Nasopharyngitis | 4% |
| Bronchitis | 3% |
| Sinusitis | 3% |
| Constipation | 3% |
| Dyspepsia | 3% |
| Nausea | 2% |
| Edema Peripheral | 2% |
| Pain in Extremity | 2% |
| Additional adverse reactions reported for meloxicam: | |
| Body as a Whole | allergic reaction, face edema, fatigue, fever, hot flushes, malaise, syncope, weight decrease, weight increase |
| Cardiovascular | angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis |
| Central and Peripheral Nervous System | convulsions, paresthesia, tremor, vertigo |
| Gastrointestinal | colitis, dry mouth, duodenal ulcer, eructation, esophagitis, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenal ulcer, hemorrhagic gastric ulcer, intestinal perforation, melena, pancreatitis, perforated duodenal ulcer, perforated gastric ulcer, stomatitis ulcerative |
| Heart Rate and Rhythm | arrhythmia, palpitation, tachycardia |
| Hematologic | agranulocytosis, leukopenia, purpura, thrombocytopenia |
| Immune System | anaphylactoid reactions (including shock) |
| Liver and Biliary System | ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis, jaundice, liver failure |
| Metabolic and Nutritional | dehydration |
| Psychiatric | abnormal dreaming, alterations in mood (such as mood elevation), anxiety, appetite increased, confusion, depression, nervousness, somnolence, |
| Respiratory | asthma, bronchospasm, dyspnea |
| Skin and Appendages | alopecia, angioedema, bullous eruption, erythema multiforme, exfoliative dermatitis, photosensitivity reaction, pruritus, Stevens-Johnson Syndrome, toxic epidermal necrolysis, sweating increased, urticaria |
| Special Senses | abnormal vision, conjunctivitis, taste perversion, tinnitus |
| Urinary System | albuminuria, acute urinary retention, BUN increased, creatinine increased, hematuria, interstitial nephritis, renal failure, |
Drug Interactions
See Table 3 for clinically significant drug interactions with meloxicam.
Table 3 : Clinically Significant Drug Interactions with meloxicam
| Drugs That Interfere with Hemostasis | |
| Clinical Impact |
|
| Intervention : | Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see WARNINGS AND PRECAUTIONS]. |
| Aspirin | |
| Clinical Impact: | Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see WARNINGS AND PRECAUTIONS]. Meloxicam is not a substitute for aspirin for cardiovascular prophylaxis. |
| Intervention: | Concomitant use of meloxicam and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS]. |
| ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers | |
| Clinical Impact: |
|
| Intervention |
|
| Diuretics | |
| Clinical Impact : | Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
| Intervention: | Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
| Digoxin | |
| Clinical Impact | The concomitant use of meloxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
| Intervention | During concomitant use of meloxicam and digoxin, monitor serum digoxin levels |
| Methotrexate | |
| Clinical Impact | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
| Intervention | During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
| Cyclosporine | |
| Clinical Impact | Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. |
| Intervention | During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
| NSAIDs and Salicylates | |
| Clinical Impact: | Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see WARNINGS AND PRECAUTIONS]. |
| Intervention: | The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
| Pemetrexed | |
| Clinical Impact: | Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
| Intervention | During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination halflives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
Warnings
Included as part of the PRECAUTIONS section.
Precautions
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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, such as meloxicam, increases the risk of serious gastrointestinal (GI) events [see WARNINGS AND PRECAUTIONS].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see CONTRAINDICATIONS].
Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of meloxicam capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If meloxicam capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And Perforation
NSAIDs, including meloxicam, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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 meloxicam capsules. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors For GI Bleeding, Ulceration, And Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies To Minimize The GI Risks In NSAID-Treated Patients
- Use the lowest effective dosage for the shortest possible duration.
- Avoid administration of more than one NSAID at a time.
- Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For high risk patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
- Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
- If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue meloxicam capsules until a serious GI adverse event is ruled out.
- In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see DRUG INTERACTIONS].
Hepatotoxicity
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flulike” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue meloxicam capsules immediately, and perform a clinical evaluation of the patient.
Hypertension
NSAIDs, including meloxicam, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see DRUG INTERACTIONS].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure And Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see DRUG INTERACTIONS].
Avoid the use of meloxicam capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If meloxicam capsules is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Renal Toxicity And Hyperkalemia
Renal Toxicity
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 may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of meloxicam capsules in patients with advanced renal disease. The renal effects of meloxicam capsules may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating meloxicam capsules. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of meloxicam capsules [see DRUG INTERACTIONS]. Avoid the use of meloxicam capsules in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If meloxicam capsules are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
Anaphylactic Reactions
Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Seek emergency help if an anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirinsensitive patients, meloxicam is contraindicated in patients with this form of aspirin sensitivity [see CONTRAINDICATIONS]. When meloxicam capsules are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin Reactions
NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of meloxicam capsules at the first appearance of skin rash or any other sign of hypersensitivity. Meloxicam capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [see CONTRAINDICATIONS].
Drug Reaction With Eosinophilia And Systemic Symptoms (DRESS)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as meloxicam. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue meloxicam and evaluate the patient immediately.
Fetal Toxicity
Premature Closure Of Fetal Ductus Arteriosus
Avoid use of NSAIDS, including meloxicam capsules, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including meloxicam, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including meloxicam capsules, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.
Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit meloxicam capsules use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if meloxicam capsules treatment extends beyond 48 hours. Discontinue meloxicam capsules if oligohydramnios occurs and follow up according to clinical practice [see Use In Specific Populations].
Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect upon erythropoiesis. If a patient treated with meloxicam capsules have any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including meloxicam, may increase the risk of bleeding events. Concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see DRUG INTERACTIONS].
Masking Of Inflammation And Fever
The pharmacological activity of meloxicam capsules in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see WARNINGS AND PRECAUTIONS].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Patients, families, or their caregivers should be informed of the following information before initiating therapy with meloxicam capsules and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see WARNINGS AND PRECAUTIONS].
Gastrointestinal Bleeding, Ulceration, And Perforation
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see WARNINGS AND PRECAUTIONS].
Hepatotoxicity
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop meloxicam capsules and seek immediate medical therapy [see WARNINGS AND PRECAUTIONS].
Heart Failure And Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see WARNINGS AND PRECAUTIONS].
Anaphylactic Reactions
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Serious Skin Reactions, Including DRESS
Advise patients to stop taking meloxicam capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see WARNINGS AND PRECAUTIONS].
Fetal Toxicity
Inform pregnant women to avoid use of meloxicam capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with meloxicam capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Avoid Concomitant Use Of NSAIDs
Inform patients that the concomitant use of meloxicam capsules with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use Of NSAIDs And Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly with meloxicam capsules until they talk to their healthcare provider [see DRUG INTERACTIONS].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
Carcinogenesis
There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.8- and 3.9-times, respectively, the maximum recommended daily dose (MRDD) of 10 mg of meloxicam capsules based on body surface area (BSA) comparison).
Mutagenesis
Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow.
Impairment Of Fertility
In previous studies of meloxicam, there was no impairment of male or female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 8.7 and 4.8-times, respectively, the MRDD based on BSA comparison).
Use In Specific Populations
Pregnancy
Risk Summary
Use of NSAIDs, including meloxicam, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of meloxicam capsules use between about 20 and 30 weeks of gestation, and avoid meloxicam capsules use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).
Premature Closure Of Fetal Ductus Arteriosus
Use of NSAIDs, including meloxicam capsules, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.
Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.
In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent 1- and 10-times, respectively, the maximum recommended daily dose (MRDD) of meloxicam capsules. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 116-times the MRDD. In pre- and post-natal reproduction studies, increased incidence of dystocia, delayed parturition, and decreased offspring survival were observed in rats treated with meloxicam at an oral dose equivalent to 0.12-times the MRDD of meloxicam capsules. No teratogenic effects were observed in rats treated with meloxicam during organogenesis at an oral dose equivalent to 3.9- times the MRDD [see Data].
Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Premature Closure Of Fetal Ductus Arteriosus
Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including meloxicam capsules, can cause premature closure of the fetal ductus arteriosus (see Data).
Oligohydramnios/Neonatal Renal Impairment
If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If meloxicam capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue meloxicam capsules and follow up according to clinical practice (see Data).
Labor Or Delivery
There are no studies on the effects of meloxicam capsules during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Human Data
Premature Closure Of Fetal Ductus Arteriosus
Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment
Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.
Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the fullterm infant exposed to NSAIDs through maternal use is uncertain.
Animal Data
Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (3.9-times the maximum recommended daily dose (MRDD) of 10 mg of meloxicam capsules based on body surface area [BSA] comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (116-times the MRDD based on BSA comparison). The no effect level was 20 mg/kg/day (39-times the MRDD based on BSA comparison). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (1- and 10-times the MRDD based on BSA comparison) when administered throughout organogenesis.
Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.12-times the MRDD based on BSA comparison).
Lactation
Risk Summary
There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for meloxicam capsules and any potential adverse effects on the breastfed infant from the meloxicam capsules or from the underlying maternal condition
Data
Animal Data
Meloxicam was excreted in the milk of lactating rats at concentrations higher than those in plasma.
Females And Males Of Reproductive Potential
Infertility
Females
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including meloxicam, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including meloxicam, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Pediatric Use
The safety and effectiveness of meloxicam capsules in pediatric patients has not been established.
Geriatric Use
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see WARNINGS AND PRECAUTIONS]. Of the total number of patients in clinical studies of meloxicam capsules, 291 were age 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Hepatic Impairment
No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Because meloxicam is significantly metabolized in the liver; use meloxicam capsules in patients with severe hepatic impairment only if the benefits are expected to outweigh the risks. If meloxicam capsules are used in patients with severe hepatic impairment, monitor patients for signs of worsening liver function [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].
Renal Impairment
No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of meloxicam capsules in subjects with severe renal impairment is not recommended. In a previous study, the free C plasma concentrations following a single dose of meloxicam were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Therefore, the maximum meloxicam capsules dosage in this population is 5 mg per day. Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].
Overdose
Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see WARNINGS AND PRECAUTIONS].
There is limited experience with meloxicam overdose. In four reported cases of meloxicam overdose, patients took 6 to 11 times the highest available dose of meloxicam tablets (15 mg); all recovered. Cholestyramine is known to accelerate the clearance of meloxicam.
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Accelerated removal of meloxicam by 4 g oral doses of cholestyramine given three times a day was demonstrated in a previous clinical trial. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment contact a poison control center (1 800-222-1222).
Contraindications
Meloxicam capsules are contraindicated in the following patients:
- Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product [see WARNINGS AND PRECAUTIONS]
- History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see WARNINGS AND PRECAUTIONS]
- In the setting of coronary artery bypass graft (CABG) surgery [see WARNINGS AND PRECAUTIONS]
Clinical Pharmacology
Mechanism Of Action
Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of meloxicam, like that of other NSAIDs, may be related to prostaglandin synthetase (cyclo-oxygenase) inhibition.
Pharmacokinetics
Absorption
The absolute bioavailability of meloxicam capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Following single intravenous doses, dose-proportional pharmacokinetics were shown in the range of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of meloxicam capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean Cmax was achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. With multiple dosing, steady state concentrations were reached by Day 5. A second meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting biliary recycling.
Table 1 : Single Dose and Steady State Pharmacokinetic Parameters for Oral 7.5 mg and 15 mg Meloxicam (Mean and % CV)1
| Steady State | Single Dose | ||||
| Pharmacokinetic Parameters (% CV | Healthy male adulis (Fed)2 | Elderly males (Fed)2 | Elderly females (Fed)2 | Renal failure (Fasted) | Hepatic insufficiency (Fasted) |
| 7.5 mg3 tablets | 15 mg capsules | L5 mg capsules | 15 mg capsules | 15 mg capsules | |
| N | 18 | 5 | 8 | 12 | 12 |
| Cmax [μg/mL] | 1.05 (20) | 2.3 (59) | 3.2 (24) | 0.59 (36) | 0.84 (29) |
| tmax [h] | 4.9 (8) | 5 (12) | 6 (27) | 4 (65) | 10 (87) |
| t½ [h] | 20.1(29) | 21(34) | 24 ( 34) | 18 (46) | 16 (29) |
| CLf [mL/min] | 8.8 (29) | 9.9 (76) | 5.1 (22) | 19 (43) | 11 (44) |
| Vz/f4[L] | 14.7 (32) | 15 (42) | 10 (30) | 26 (44) | 14 (29) |
| 1The parameter values in the Table are from various studies 2not under high fat conditions 3Meloxicam tablets 4Vz/f =Dose/(AUC•Kel) |
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Food And Antacid Effects
Administration of meloxicam capsules following a high fat breakfast (75 g of fat) resulted in mean peak drug levels (i.e., Cmax) being increased by approximately 22% while the extent of absorption (AUC) was unchanged. The time to maximum concentration (Tmax) was achieved between 5 and 6 hours.
No pharmacokinetic interaction was detected with concomitant administration of antacids. Based on these results, Meloxicam ablets can be administered without regard to timing of meals or concomitant administration of antacids.
Distribution
The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~ 99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~ 99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam.
Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown.
Metabolism
Meloxicam is almost completely metabolized to four pharmacologically inactive metabolites. The major metabolite, 5′-carboxy meloxicam (60% of dose), from P-450 mediated metabolism was formed by oxidation of an intermediate metabolite 5′-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). Invitro studies indicate that cytochrome P-450 2C9 plays an important role in this metabolic pathway with a minor contribution of the CYP 3A4 isozyme. Patients’ peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively.
Excretion
Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6% and 13% of the dose were found in urine in the form of meloxicam, and the 5′-hydroxymethyl and 5′-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%.
The mean elimination half-life (t½) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min.
Special populations
Geriatric
Elderly males ( ≥ 65 years of age) exhibited meloxicam plasma concentrations and steady state pharmacokinetics similar to young males. Elderly females ( ≥ 65 years of age) had a 47% higher AUCss and 32% higher Cmax,ss, as compared to younger females ( ≤ 55 years of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients.
Gender
Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg meloxicam, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs. 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cmax or Tmax across genders
Hepatic Insufficiency
Following a single 15 mg dose of meloxicam there was no marked difference in plasma concentrations in subjects with mild (Child-Pugh Class I) and moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic insufficiency. No dose adjustment is necessary in mild to moderate hepatic insufficiency. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied.
Renal Insufficiency
Meloxicam pharmacokinetics have been investigated in subjects with different degrees of renal insufficiency. Total drug plasma concentrations decreased with the degree of renal impairment while free AUC values were similar. Total clearance of meloxicam increased in these patients probably due to the increase in free fraction leading to an increased metabolic clearance. There is no need for dose adjustment in patients with mild to moderate renal failure (CrCL > 15 mL/min). Patients with severe renal insufficiency have not been adequately studied. The use of, meloxicam in subjects with severe renal impairment is not recommended (see WARNINGS, Advanced Renal Disease).
Hemodialysis
Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable.
Clinical Trials
Osteoarthritis And Rheumatoid Arthritis
The use of meloxicam for the treatment of the signs and symptoms of osteoarthritis of the knee and hip was evaluated in a 12-week double-blind controlled trial. Meloxicam (3.75 mg, 7.5 mg and 15 mg daily) was compared to placebo. The four primary endpoints were investigator’s global assessment, patient global assessment, patient pain assessment, and total WOMAC score (a self-administered questionnaire addressing pain, function and stiffness). Patients on meloxicam 7.5 mg daily and meloxicam 15 mg daily showed significant improvement in each of these endpoints compared with placebo.
The use of meloxicam for the management of signs and symptoms of osteoarthritis was evaluated in six double-blind, active-controlled trials outside the U.S. ranging from 4 weeks to 6 months duration. In these trials, the efficacy of meloxicam, in doses of 7.5 mg/day and 15 mg/day, was comparable to piroxicam 20 mg/day and diclofenac SR 100 mg/day and consistent with the efficacy seen in the U.S. trial.
The use of meloxicam for the treatment of the signs and symptoms of rheumatoid arthritis was evaluated in a 12-week double-blind, controlled multinational trial. Meloxicam (7.5 mg, 15 mg and 22.5 mg daily) was compared to placebo. The primary endpoint in this study was the ACR20 response rate, a composite measure of clinical, laboratory and functional measures of RA response. Patients receiving meloxicam 7.5 mg and 15 mg daily showed significant improvement in the primary endpoint compared with placebo. No incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose. Higher doses of meloxicam (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore the daily dose of meloxicam should not exceed 15 mg.