Naproxen Delayed-Release Tablets - Uses, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Overview

Naproxen delayed-release tablets are designed to help manage the symptoms of ankylosing spondylitis, a form of inflammatory arthritis that impacts the spine. Gradually releasing the medication over time, these tablets offer extended relief from pain, stiffness, and inflammation linked to the condition. Their slow-release formulation ensures consistent symptom management throughout the day. The US FDA (United States Food and Drug Administration) approved Naproxen's delayed-release tablets on July 2, 2024.

Drug Group

Naproxen delayed-release tablets belong to the drug group known as nonsteroidal anti-inflammatory drugs (NSAIDs). Specifically, they are part of the propionic acid derivatives subgroup within NSAIDs.

Indications

Naproxen delayed-release tablets are indicated for the relief of the signs and symptoms of:

• Rheumatoid Arthritis: An autoimmune disorder causing persistent joint inflammation resulting in discomfort, edema, and potential joint damage.

• Osteoarthritis: A degenerative joint disease where cartilage wears down over time, causing pain, stiffness, and reduced mobility.

• Ankylosing Spondylitis: An arthritis that primarily affects the back, leading to inflammation, pain, and potentially fusion of the vertebrae.

• Polyarticular Juvenile Idiopathic Arthritis: A type of arthritis that affects five or more joints in children, causing pain, swelling, and stiffness.

Dosage Forms and Available Strengths

Naproxen delayed-release tablets are available in the following strengths:

• 375 mg (Milligrams): White, oval, biconvex-coated tablets imprinted with "NPR EC 375" on one side.

• 500 mg: White, oblong coated tablets imprinted with "NPR EC 500" on one side.

For Patients

What Is the Ankylosing Spondylitis?

Ankylosing spondylitis (AS) is an inflammatory arthritis primarily affecting the spine, although other joints can be involved. It results in inflammation of the vertebral joints in the spine, leading to severe, chronic pain and discomfort. Some of the spine's vertebrae may fuse due to the inflammation over time, resulting in a loss of flexibility and potentially leading to a hunched posture. Symptoms often include back pain and stiffness that improve with exercise but not with rest and can worsen in the morning or following inactive periods. AS can also affect other body parts, including the eyes, heart, and lungs. Although the precise cause is uncertain, genetics is a major factor, particularly the presence of the HLA-B27 or human leukocyte antigen B27 gene. Treatment goals are to keep patients mobile and manage symptoms through medications, physical therapy, and exercise.

How Do the Naproxen Delayed-Release Tablets Work?

Naproxen delayed-release tablets are designed to release the medication gradually over time. The delayed-release formulation is coated to protect the drug from stomach acid and ensure it dissolves in the small intestine's more neutral pH (potential of hydrogen) environment. This approach helps to reduce potential stomach irritation and provides a controlled release of Naproxen, leading to sustained pain relief and anti-inflammatory effects.

What Is the Dosage of the Naproxen Delayed-Release Tablets?

Common dosages are:

• For Osteoarthritis, Rheumatoid Arthritis, or Ankylosing Spondylitis: Usually, 500 to 750 mg is the dosage, taken twice daily.

• For Acute Gout: The initial dose is usually 750 mg, then 250 mg every eight hours until the attack stops.

• For Other Conditions: Depending on the patient's reaction and the degree of symptoms, the dosage may change.

How Is Naproxen Delayed-Release Tablet Administered?

Naproxen delayed-release tablets are administered orally and should be swallowed whole with a full glass of water. It is crucial to avoid chewing, crushing, or breaking the tablets. The medication is typically taken twice daily, either with or without food. Using it with milk or food may help lessen an uncomfortable stomach. Consistency in timing is key, so taking the tablets at the exact times each day helps maintain even levels in the body.

What Are the Side Effects of Naproxen Delayed-Release Tablets?

Serious Side Effects:

• New or worsening high blood pressure.

• Heart failure.

• Liver problems, including liver failure.

• Kidney problems, including kidney failure.

• Low red blood cell count (anemia).

• Life-threatening skin reactions.

• Life-threatening allergic reactions.

Other Side Effects of NSAIDs:

• Stomach pain.

• Constipation.

• Diarrhea.

• Gas.

• Heartburn.

• Nausea.

• Vomiting.

• Dizziness.

Seek Emergency Help Immediately If Experiencing:

• Shortness of breath or trouble breathing

• Chest pain.

• Weakness in one part or side of the body.

• Slurred speech.

• Swelling of the face or throat.

Contact Healthcare Provider Immediately If Experiencing:

• Nausea.

• Increased tiredness or weakness.

• Diarrhea.

• Itching.

• Yellowing of the skin or eyes.

• Indigestion or stomach pain.

• Flu-like symptoms.

• Vomiting blood.

• Blood in bowel movements or black, sticky stool.

• Unusual weight gain.

• Skin rash or blisters with fever.

• Swelling of the arms, legs, hands, or feet.

What Are the Things to Inform the Doctor Before Taking Naproxen Delayed-Release Tablets?

Before taking Naproxen delayed-release tablets:

1. Allergies and Medications:

• Notify the pharmacist and physician of any allergies to Naproxen, Aspirin, Ibuprofen, Ketoprofen, or other medications.

• Provide a list of all prescriptions and any available nonprescription drugs, vitamins, dietary supplements, and herbal products taken or planned to be taken.

• Include medications such as ACE (angiotensin-converting enzyme) inhibitors, ARBs (angiotensin receptor blockers), beta-blockers, diuretics, cyclosporine, Digoxin, and others.

2. Drug Interactions:

• Avoid combining nonprescription Naproxen with other pain medications unless advised by a healthcare provider.

• Mention if antacids or sucralfate are being taken, as the doctor may need to adjust the medication or monitor for side effects.

3. Health Conditions:

• Notify the doctor if you are following a low-sodium diet or if you have any significant health conditions, such as asthma, heart failure, kidney disease, swelling, anemia, or others.

4. Pregnancy and Breastfeeding:

• Inform the doctor if pregnant, planning to become pregnant, or breastfeeding. Naproxen may harm the fetus and cause delivery problems if taken after 20 weeks of pregnancy.

• Contact the doctor immediately if pregnancy occurs while taking Naproxen.

• Naproxen may temporarily affect fertility; discuss any concerns about fertility with the doctor.

5. Older Adults: For individuals 65 or older, discuss the risks and benefits of taking Naproxen with the doctor. Generally, lower doses are recommended for shorter periods because side effects are more likely to occur.

6. Surgery: Inform the doctor or dentist about Naproxen use before surgery, including dental procedures.

Dietary Considerations

Patients can continue with the normal diet unless otherwise instructed by a doctor.

Missed Dose

Take the missed dose as soon as a person remembers it. Refrain from taking the missing dose if it is time for the next one, and resume the regular schedule. Never take two doses to make up for one that is missed.

Overdose

Symptoms of an acute NSAID overdose typically include lethargy, drowsiness, nausea, vomiting, and epigastric pain, which usually improve with supportive care. Gastrointestinal bleeding can occur, and in rare cases, hypertension, acute renal failure, respiratory depression, and coma may also happen. High and early blood levels are expected due to the rapid absorption of Naproxen sodium. Convulsions have been reported, though their connection to the drug is unclear. The exact, life-threatening dose is unknown.

Management:

General Treatment: Provide symptomatic and supportive care. No specific antidotes are available.

Decontamination:

• Emesis: Emesis is vomiting or inducing vomiting. Consider it if it is within four hours of ingestion.

• Activated Charcoal: Administer 60 to 100 grams for adults and one to two grams per kg (kilogram) for children.

• Osmotic Cathartic: May be used in symptomatic patients.

• Other Measures: Forced diuresis (increasing urine output to remove toxins), urine alkalinization (making urine less acidic to aid drug elimination), hemodialysis (filtering blood to remove waste when kidneys fail), or hemoperfusion (removing toxins from blood using a device) may not be effective due to high protein binding.

For further guidance on overdose treatment, contact a poison control center.

Storage and Handling

Naproxen delayed-release tablets have two strengths. The 375 mg tablets are white, oval, biconvex, and coated, with "NPR EC 375" imprinted on one side, and are packaged in light-resistant bottles of 100. The 500 mg tablets are white, oblong, coated, and imprinted with "NPR EC 500" on one side, also packaged in light-resistant bottles of 100. Both formulations should be stored at 15 to 30 degrees Celsius °C (59 to 86 degrees Fahrenheit or °F) in well-closed, light-resistant containers.

For Doctors

Description:

Naproxen Delayed-Release Tablets: These white tablets contain 375 mg or 500 mg of Naproxen and have an enteric coating that dissolves above pH 6.

Chemical Details:

Naproxen: (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid, molecular weight 230.26, formula C14H14O3.

Inactive Ingredients: Croscarmellose sodium, povidone, magnesium stearate, methacrylic acid copolymer, talc, triethyl citrate, sodium hydroxide, purified water.

Warnings and Precautions

• Cardiovascular Thrombotic Events: Clinical trials show that COX-2 selective and nonselective NSAIDs, including Naproxen, can increase the risk of serious cardiovascular events like heart attack and stroke, especially at higher doses and early in treatment. Those with existing cardiovascular disease or those at risk have a higher incidence of these events. To minimize risk, use the lowest effective dose for the shortest time. Be vigilant for cardiovascular issues, even without prior symptoms. Combining Aspirin with NSAIDs also raises the risk of severe gastrointestinal (GI) events.

• Gastrointestinal Bleeding, Ulceration, and Perforation: NSAIDs, including Naproxen, can cause severe and potentially fatal GI issues like bleeding, ulcers, and perforation. These effects can occur without warning. Risk factors include a history of GI bleeding, long-term NSAID use, and concurrent use of Aspirin, anticoagulants, or SSRIs (selective serotonin reuptake inhibitors), as well as smoking, alcohol, advanced age, and poor health. To reduce GI risks, use the lowest effective dose for the shortest time, avoid using multiple NSAIDs, and watch for signs of GI problems. Discontinue Naproxen immediately if a serious GI event occurs.

• Hepatotoxicity: NSAIDs, including Naproxen, can cause liver damage, including severe conditions like fulminant hepatitis or liver failure. Watch for flu-like symptoms, right upper quadrant pain, exhaustion, diarrhea, itching, and jaundice. Discontinue Naproxen immediately and seek a clinical evaluation if liver issues arise.

• Hypertension: NSAIDs may cause preexisting hypertension to worsen or develop hypertension from scratch, which raises the risk of cardiovascular events. Patients taking ACE inhibitors, thiazide diuretics, or when using NSAIDs, loop diuretics may respond less well to these treatments. Monitor blood pressure during the initiation and throughout NSAID therapy.

• Heart Failure and Edema: NSAIDs, including Naproxen, can cause fluid retention and edema and increase the risk of heart failure. This risk is higher in patients with heart failure, and NSAID use should be avoided in these patients unless the benefits outweigh the risks. Patients should be watched for indications of deteriorating heart failure, especially if Naproxen is used in patients with severe heart failure.

• Renal Toxicity and Hyperkalemia: Long-term NSAID use can lead to renal papillary necrosis and other kidney injuries, especially in those with conditions like diuretic use, hypovolemia, heart failure, liver disease, or existing kidney issues. Adjust volume status and monitor kidney function before starting Naproxen in these patients. NSAIDs can also cause hyperkalemia, even in those with normal kidney function.

• Anaphylactic Reactions: Patients with Aspirin-sensitive asthma and those who do not know they are allergic to Naproxen may experience severe anaphylactic events when using Naproxen. In the event of an anaphylactic response, get emergency assistance.

• Exacerbation of Asthma Related to Aspirin Sensitivity: Patients with Aspirin-sensitive asthma, which can include chronic rhinosinusitis complicated by nasal polyps, severe bronchospasm, and intolerance to Aspirin and other NSAIDs, may experience exacerbated symptoms when using Naproxen. Avoid use in these patients. Monitor patients with preexisting asthma for changes in symptoms.

• Serious Skin Reactions: NSAIDs like Naproxen can cause severe, life-threatening skin reactions, such as exfoliative dermatitis, TEN (toxic epidermal necrolysis), and SJS (Stevens-Johnson syndrome), which may occur without warning. Inform patients of symptoms and discontinue use immediately if a skin rash or hypersensitivity occurs. Those with a history of severe skin reactions to NSAIDs should avoid Naproxen.

• Premature Closure of Fetal Ductus Arteriosus: Premature closure of the fetal ductus arteriosus may result from Naproxen. Pregnant women should stop using NSAIDs, such as Naproxen, at 30 weeks of gestation (the third trimester).

• Hematologic Toxicity: NSAIDs can cause anemia, which may result from blood loss, fluid retention, or an effect on erythropoiesis. Monitor hemoglobin or hematocrit in patients with signs or symptoms of anemia. NSAIDs can also increase the risk of bleeding events, especially in patients with coagulation disorders or those taking anticoagulants, antiplatelet agents, SSRIs, or SNRIs.

• Masking of Inflammation and Fever: NSAIDs, due to their anti-inflammatory and antipyretic properties, can mask the signs of infection, potentially delaying diagnosis and treatment.

• Long-Term Use and Laboratory Monitoring: Due to the risk of serious GI bleeding, hepatotoxicity, and renal injury without warning symptoms, consider periodic monitoring. of patients on long-term NSAID treatment with a complete blood count (CBC) and chemistry profile.

What Are the Pharmacological Actions of Naproxen Delayed-Release Tablets?

Mechanism of Action: Naproxen has pain-relieving, anti-inflammatory, and fever-reducing effects. It blocks the cyclooxygenase enzymes (COX-1 and COX-2) involved in making pain-causing chemicals called prostaglandins. By reducing prostaglandin levels, Naproxen helps lower pain and inflammation.

Pharmacokinetics:

• Absorption: Naproxen is quickly and fully absorbed, with about 95 percent bioavailability. Due to delayed release, Naproxen delayed-release tablets reach peak levels in four to six hours.

• Distribution: The body widely distributes Naproxen, mostly bound to albumin. Its distribution volume is 0.16 L/kg.

• Elimination: Naproxen is mainly metabolized in the liver and excreted in the urine. The half-life is 12 to 17 hours, and about 95 percent is excreted in the urine.

Special Populations:

• Pediatrics: Similar plasma levels and half-lives as adults when dosed appropriately.

• Elderly: increased unbound Naproxen, though the total plasma concentration remains unchanged.

• Hepatic Impairment: reduced total plasma concentration but increased unbound Naproxen.

• Renal Impairment: Potential for accumulation of Naproxen metabolites in severe cases.

Drug Interactions:

Aspirin: May reduce Naproxen protein binding without altering free Naproxen clearance.

Non-Clinical Toxicity:

In a two-year study with rats, no evidence of cancer was found at Naproxen doses up to 24 mg/kg/day, which is 0.16 times the maximum recommended human dose. While Naproxen tested positive in an in vivo chromatid exchange assay, it was not mutagenic in bacterial reverse mutation tests. Additionally, studies on fertility showed no adverse effects in male and female rats given up to 20 mg/kg of Naproxen, which is 0.13 times the human maximum dose.

What Are the Contraindications of Naproxen Delayed-Release Tablets?

Naproxen delayed-release tablets should not be used in the following patients:

• Those with known hypersensitivity to Naproxen or any components of the drug, including severe reactions such as anaphylaxis or serious skin reactions.

• For people who have previously experienced urticaria, asthma, or other allergic reactions after using Aspirin or other NSAIDs, severe and sometimes fatal anaphylactic reactions have been reported in these cases.

• Patients undergoing or who have undergone coronary artery bypass graft (CABG) surgery.

What Are the Drug Interactions of Naproxen Delayed-Release Tablets?

The drug interactions are:

• ACE (angiotensin-converting enzyme)-Inhibitors.

• Antacids and Sucralfate.

• Aspirin.

• Cholestyramine.

• Diuretics.

• Lithium.

• Methotrexate.

• Warfarin.

• SSRIs.

• Beta-Blockers.

• Probenecid.

• H2-Blockers.

Clinical Studies

Naproxen has demonstrated effectiveness in managing ankylosing spondylitis, a type of arthritis that primarily affects the spine and can lead to pain and stiffness. Clinical studies have shown that Naproxen significantly reduces night pain, morning stiffness, and pain at rest associated with ankylosing spondylitis. Naproxen was as effective as Aspirin in controlling symptoms in these studies but with fewer gastrointestinal side effects.

Patients taking Naproxen for ankylosing spondylitis often experience reduced pain and stiffness and increased mobility, leading to better overall function. The medication's effectiveness in managing these symptoms makes it an important option for patients with this chronic condition. Additionally, compared to other NSAIDs, Naproxen generally has a lower incidence of milder gastrointestinal side effects, such as nausea and dyspepsia.

Use in Specific Populations

• Pregnancy: Avoid using NSAIDs like Naproxen delayed-release tablets after 30 weeks of pregnancy because they can cause problems like premature closure of the fetal ductus arteriosus. There are no well-controlled studies on these medications in pregnant women, but animal studies suggest possible risks. NSAIDs can also cause issues during labor, such as delayed delivery and stillbirth.

• Lactation: Naproxen can be found in small amounts in breast milk. Consider the benefits of breastfeeding versus any potential risks to the baby from the medication.

• Infertility: NSAIDs may delay ovulation and potentially cause temporary infertility. If an individual has trouble conceiving, they might need to stop using NSAIDs.

• Pediatric Use: Safety and effectiveness in children under two years old have not been established. Dosing should be based on specific recommendations for children over two.

• Geriatric Use: Older patients may be more susceptible to NSAID side effects. Use lower doses and monitor for adverse effects, especially gastrointestinal or renal issues.

• Hepatic or Renal Impairment: In patients with existing liver or kidney issues, closely evaluate liver and renal function and adjust dosages as needed.