Naproxen - Uses, Side Effects and Precautions

Overview:

Naproxen is used to treat diseases of the joints, such as rheumatoid arthritis, osteoarthritis, and mild to moderate pain. They can also treat conditions, including menstrual pain. It belongs to the group of NSAIDs, and initially, it was approved for prescription use and then for over-the-counter (OTC) use. It can effectively manage acute pain and pain related to rheumatic diseases.

Due to its overall tolerability and effectiveness, Naproxen is considered the first-line treatment in various cases like osteoarthritis, acute gout arthritis, dysmenorrhea, and musculoskeletal inflammation and pain. Naproxen was approved by the FDA (Food and Drug Administration) on February 17th, 2006.

Drug Group:

Naproxen belongs to the group of NSAIDs (non-steroidal anti-inflammatory drugs). These are drugs that are used to relieve pain, reduce inflammation, and lower the temperature. NSAIDs are available as tablets, capsules, suppositories, creams, gels, and injections.

The main types of NSAIDs are;

• Naproxen.

• Ibuprofen.

• Diclofenac.

• Celecoxib.

• Mefenamic acid.

• Etoricoxib.

• Indomethacin.

• High-dose Aspirin.

What Is Naproxen Used For?

Naproxen can be used for the following conditions:

• Rheumatoid arthritis.

• Osteoarthritis.

• Ankylosing spondylitis.

• Juvenile arthritis.

• Tendonitis.

• Bursitis.

• Gout.

• Muscle aches.

• Strains and sprains.

• Headaches.

• Dental pain.

• Menstrual cramps.

• Primary dysmenorrhea.

• Fever.

• It is also used to treat migraines in combination with Sumatriptan.

• Naproxen, in combination with Esomeprazole, can be used to lower the risk of developing gastric ulcers.

How Does Naproxen Work?

Naproxen is an NSAID that temporarily stops the hormones responsible for the inflammation and pain in the body. They work by reducing the chemicals that cause pain and inflammation. The chemicals that cause pain and inflammation are prostaglandins. Naproxen stops the cyclo-oxygenase enzymes responsible for prostaglandins' production, resulting in reduced concentrations of prostaglandins. As a result, pain and inflammation are relieved.

Dosage and Administration:

General Dosing Instructions for Naproxen:

The doctor must consider the risk-benefit ratio of Naproxen before recommending it to the patient. In addition, the alternative treatment options must be carefully evaluated before administering Naproxen. The lowest possible dose of the drug must be used for the shortest possible duration keeping in mind the patient’s treatment goals. The dosage and frequency can be adjusted according to the patient’s needs. It is important to note that the tablet must be swallowed entirely without crushing, breaking, or chewing it to maintain its integrity. The patient must avoid using Naproxen products concomitantly as they are present in the blood plasma in the form of Naproxen ions.

Recommended Dosages:

The dosage of this medicine varies from one patient to the other and also depends on the medical condition. The dosages are described below:

Strength and Dosage Forms:

Naproxen controlled-release tablets can be purchased in the following dosage forms and strengths:

• 375 mg white capsule-shaped tablet with “N” embossed on one side and “375” on the other side.

• 500 mg white capsule-shaped tablet with “N” embossed on one side and “500” on the other side.

• 750 mg white capsule-shaped tablet with “N” embossed on one side and “500” on the other side.

For Patients:

How Should the Patient Take Naproxen?

The patient needs to take Naproxen after having food or a glass of milk to prevent any stomach upset problems. Naproxen must be taken according to the dosage and timings prescribed by the doctor. Do not take any antacids within two hours of taking Naproxen. Avoid consuming alcohol while taking Naproxen because it can increase the risk of problems related to the stomach. The patient needs to take this tablet as a whole. Do not break or crush the tablet. If the patient takes the suspension, one must mix it well before consuming it. Patients with arthritis might notice that their symptoms resolve within one or two weeks.

Missed Dose:

The patient must ensure that he takes the missed dose immediately unless it is time for the next dose. Do not combine two Naproxen doses to compensate for the missed dose.

What Should One Inform the Doctor Before Consuming Naproxen?

Before taking Naproxen, the patient must inform the doctor if he or she is:

• Allergic to Naproxen or any of its ingredients.

• Taking or planning to take prescription or over-the-counter drugs like the following:

  • Benazepril.

  • Moexipril.

  • Azilsartan.

  • Olmesartan.

  • Labetalol.

  • Metoprolol.

  • Diuretics.

  • Lithium.

• Having a low sodium diet or taking medications for asthma.

• Planning to undergo dental surgery.

Note:

• The patient must avoid taking Naproxen with other painkillers.

• Females planning to conceive must consult their doctor before taking Naproxen.

• People in the geriatric age group must be given the drug only after calculating the risk-benefit ratio.

What Are Some of the Side Effects of Naproxen?

Patients must avoid taking Naproxen or other NSAIDs before or after cardiac surgery because it poses the risk of stroke or heart failure. In addition, Naproxen can cause the following side effects:

• Worsening of high blood pressure.

• Heart failure.

• Liver problems or liver failure.

• Kidney failure.

• Anemia.

• Skin reactions.

• Allergic reactions.

• Constipation.

• Diarrhea.

• Stomachache.

• Nausea.

• Gas.

• Heartburn.

• Dizziness.

• Vomiting.

• Slurred speech.

• Shortness of breath.

• Chest pain.

• Swelling of the throat or face.

The patient must stop taking Naproxen under the following circumstances:

• Diarrhea.

• Itching.

• Presence of blood in vomit.

• Yellowish discoloration of the eyes and skin.

• Indigestion.

• Presence of blood in stools.

• Flu-like symptoms.

• Weight gain.

• Blisters with fever.

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

Safety and Effectiveness of Naproxen:

Sometimes, the doctor might recommend a particular drug for purposes other than those enlisted in the medication guide. However, the patient needs to make sure that they refrain from using the drug for a condition for which is not recommended.

For Doctors:

Indications and Usage:

Naproxen tablets are used for the management of the following:

• Osteoarthritis (a degenerative joint disease that causes joint pain and stiffness).

• Rheumatoid arthritis (an autoimmune disease that causes pain and inflammation in the joints).

• Tendinitis (inflammation of the cord that connects muscle to bone).

• Bursitis (inflammation of the fluid-filled sacs in the joints).

• Ankylosing spondylitis (inflammation of the joints of the back or spine).

• Primary dysmenorrhoea (refers to the pain that occurs during periods).

• Relief from mild or moderate pain.

Contraindications:

Naproxen is contraindicated under the following circumstances:

1. Patients with an allergy to the drug or any of its ingredients must avoid consuming Naproxen to avoid the risk of anaphylactic reactions.

2. Patients with a medical history of asthma, allergy, urticaria, or other allergic reactions after Naproxen must avoid taking it.

3. Patients must avoid taking Naproxen if they have undergone coronary artery bypass graft surgery.

Warnings and Precautions:

1) Cardiovascular Thrombotic Events:

Clinical studies have shown that if NSAIDs like Naproxen are taken for three years or more, the patient becomes more vulnerable to severe cardiovascular thrombotic events, including stroke or myocardial infarction. However, it has not been known which particular NSAIDs increase the risk of these events. Some researchers believe that an increase in cardiovascular thrombotic events occurs during the first few weeks of treatment which becomes consistent as the dose is increased. Hence, the lowest dose of the drug must be used to minimize the risk of heart-related side effects. In addition, controlled clinical studies have also reported that patients using NSAIDs post coronary artery bypass graft surgery are at a higher risk of stroke and myocardial infarction.

2) Gastrointestinal Bleeding:

Naproxen can cause the following gastrointestinal side effects:

• Inflammation.

• Ulceration.

• Bleeding.

• Esophageal perforation.

• Perforation of the small intestine, stomach, and large intestine.

Patients with a medical history of peptic ulcer are more vulnerable to developing gastrointestinal bleeding. Some crucial factors that elevate the risk of gastrointestinal bleeding include:

• Smoking.

• Alcohol.

• Concomitant use of Aspirin, anticoagulants, oral corticosteroids, or selective serotonin reuptake inhibitors.

• Old age.

• Poor general health.

The following measures help minimize the risk:

• Consume the lowest effective dose of Naproxen for a short duration.

• Avoid consuming multiple NSAIDs at a time.

• The drug must be used in high-risk patients only after carefully calculating the risk-benefit ratio.

• Notice the signs and symptoms and report them to the doctor.

3) Hepatotoxicity:

Approximately one percent of patients have reported an increase in alanine transaminase (ALT) and aspartate aminotransferase (AST) levels during the trial. In addition, fatal cases have been reported due to liver injury, including fulminant hepatitis and liver necrosis. Hence, the patient must be aware of the problems associated with liver toxicity.

4) Hypertension or High Blood Pressure:

Naproxen can initiate or worsen hypertension which can increase the risk of cardiovascular thrombotic events. Patients consuming angiotensin-converting enzyme inhibitors like thiazides or loop diuretics might present with an impaired response.

5) Cardiac Failure:

Naproxen can increase the risk of hospitalization due to heart failure. In addition, fluid retention has been noticed in some patients, which can lead to edema.

6) Renal Toxicity:

Patients consuming Naproxen for prolonged periods tend to experience renal papillary necrosis and other kidney injuries. Hence, if such patients are administered NSAIDs, a dose dependant reduction in prostaglandin formation followed by reduced renal blood flow and overt renal decompensation has been observed. Patients with preexisting kidney disease tend to experience permanent kidney dysfunction after taking NSAIDs. Hyperkalemia, or an increase in the potassium levels in the blood, has been observed in patients taking NSAIDs.

7) Anaphylactic Reactions:

Anaphylactic reactions commonly occur in patients with hypersensitivity to the drug.

8) Dermatologic Reactions:

Naproxen can induce severe dermatologic reactions, including Stevens-Johnson syndrome, exfoliative dermatitis, and toxic epidermal necrolysis. Hence, the patient must be informed about these symptoms so that he can use the drug cautiously.

9) Premature Closure of Ductus Arteriosus:

Naproxen must not be given to pregnant females during the 30th week of gestation because it can induce the premature closure of fetal ductus arteriosus.

10) Hematologic Toxicity:

NSAIDs like Naproxen can trigger anemia due to blood loss, retention of fluids, and impaired erythropoiesis. Therefore, patients with anemia must get their hemoglobin and hematocrit levels checked. In addition, Naproxen can also induce the risk of bleeding disorders if administered concomitantly with Warfarin, anticoagulants, antiplatelet agents, or serotonin reuptake inhibitors.

What Are Some of the Adverse Reactions of Naproxen?

The following adverse reactions were observed during the clinical trials and when the drug was launched in the market:

1) Gastrointestinal:

• Anorexia (a condition wherein a patient becomes obsessed about his weight and the food one eats).

• Nausea.

• Diarrhea.

• Constipation.

• Dysphagia (it is characterized by difficulties in swallowing).

• Heartburn.

• Stomatitis.

• Flatulence (gas).

• Gastritis.

• Cholecystitis (inflammation of the organ below the liver or gallbladder is known as cholecystitis).

• Cholelithiasis (presence of hardened deposits in the gallbladder).

• Stomatitis aphthous (formation of painful sores or ulcers).

• Stomatitis ulcer.

• Esophagitis.

• Gastroenteritis.

• Rectal disorder.

2) Hematological:

• Anemia.

• Ecchymosis (bruising or discoloration of the skin).

• Leukopenia (decrease in the leukocyte count)

• Increased bleeding time.

• Eosinophilia.

• Abnormal RBC (red blood cells) and WBC (white blood cell) count.

• Thrombocytopenia (reduced blood platelet count).

• Granulocytopenia (reduced granulocyte count).

3) Respiratory:

• Asthma.

• Dyspnea.

• Sinusitis.

• Bronchitis.

• Lung edema.

• Laryngitis.

• Epistaxis (nasal bleeding).

• Pneumonia.

• Respiratory distress.

• Eosinophilic pneumonitis (a type of rare infection that affects the lungs).

4) Renal:

• Dysmenorrhea (menstrual pain).

• Dysuria (pain while passing urine).

• Nocturia (urinating at night).

• Prostate disorder (disorders of the prostate gland)

• Pyelonephritis (severe infection of the kidneys).

• Urinary incontinence.

• Kidney calculus.

• Kidney failure.

• Hematuria.

• Kidney pain.

• Pyuria (presence of white blood cells or pus in the urine).

• Urinary retention.

• Uterine spasm.

• Vaginitis (inflammation of the vagina).

• Glomerulonephritis (inflammation of the filtration units of the kidneys).

• Hyperkalemia (increased potassium levels of the blood).

• Interstitial nephritis (inflammation or swelling of the kidney tubules).

• Urinary tract infections.

5) Dermatologic:

• Angiodermatitis.

• Dryness of the skin.

• Sweating.

• Ulceration of the skin.

• Acne.

• Alopecia (patchy hair loss).

• Dermatitis (inflammation of the dermis or skin)

• Contact eczema (it is characterized by the presence of rashes due to allergic reactions).

• Pruritus (an irritating sensation in which a person wants to scratch the skin).

6) Musculoskeletal:

• Bone disorders.

• Spontaneous bone fracture.

• Fibro tendinitis.

• Bone pain.

• Bursitis.

Some of the other adverse reactions are listed below:

• Cataract.

• Conjunctivitis.

• Amblyopia (reduced vision in one or both eyes from childhood)

• Angina pectoris (chest pain).

• Hyperuricemia (elevated uric acid levels in urine).

• Hyperkalemia (elevated potassium levels in blood).

• Angioneurotic edema (it is characterized by swelling beneath the skin surface).

• Pyrexia (fever).

• Arrhythmia (irregular heartbeats).

• Keratoconjunctivitis (inflammation of the conjunctiva and cornea of the eyes).

• Pain in the eyes.

Description:

Naproxen is a commonly prescribed NSAID that is available as controlled-release tablets with dosage strengths of 375 mg, 500 mg, and 750 mg. The chemical name of the drug is 2-naphthaleneacetic acid, 6-methoxy-alpha-methyl-sodium salt (S). The molecular weight of Naproxen is 252.24. The chemical formula of the drug is C14H13NaO3. It is a white or creamy, odorless, crystalline powder soluble in methanol and water.

Clinical Pharmacology:

Mechanism of Action:

Naproxen has anti-inflammatory, analgesic, and antipyretic properties, so its mechanism of action is similar to other NSAIDs. Though not much information is available regarding Naproxen’s mechanism of action, it is believed that the drug inhibits prostaglandin synthesis. Prostaglandins mediate inflammation and potentiate the action of bradykinin which induces pain. Therefore, Naproxen is an inhibitor of prostaglandin synthesis.

Pharmacokinetics:

The sodium salt form of Naproxen is well absorbed, resulting in higher plasma concentration for a particular dose. After the patient has consumed the drug, the plasma levels can be detected within 30 minutes. The plasma levels reach a peak within five hours. The termination elimination half-life of Naproxen is 15 hours.

Absorption:

The bioavailability of Naproxen is 95 % because it is completely absorbed from the gastrointestinal tract. The pharmacokinetic profile of Naproxen suggests that the absorption phase of the drug is within four to six hours. No clinically significant effects were absorbed when Naproxen was administered with or without food.

Distribution:

Naproxen’s volume of distribution is 0.16 L per kg. At therapeutic levels, it is bound to albumin.

Non-clinical Toxicology:

Carcinogenesis:

Several animal studies have been done to evaluate the carcinogenic potential of Naproxen. However, no pieces of evidence of Naproxen-induced tumorigenicity could be found.

Mutagenesis:

Several studies to check the mutagenic potential of Naproxen are still underway.

Impairment of Fertility:

Studies to evaluate the effects of Naproxen on fertility are still underway.

Chemical Taxonomy:

Drug Interactions:

• Anticoagulants:

  • The concomitant use of other anticoagulants like Warfarin and Naproxen can increase the risk of bleeding because both drugs synergize.

  • The clinical studies showed increased incidences of gastrointestinal adverse reactions when an analgesic dose of Aspirin was administered with Naproxen.

• ACE Inhibitors, Beta-Blockers, and Angiotensin Receptor Blockers:

  • Naproxen might diminish the antihypertensive effects of ACE inhibitors, beta-blockers, and angiotensin receptor blockers. Hence, patients taking such drugs must check their blood pressure regularly.

• Digoxin:

  • Concomitant administration of Digoxin and Naproxen can elevate the serum concentration and half-life of Digoxin.

• Lithium:

  • Naproxen elevates the plasma levels of Lithium and reduces renal lithium clearance.

• Methotrexate:

  • Naproxen and Methotrexate must not be administered together to avoid the risk of Methotrexate toxicity.

• Cyclosporine:

  • Naproxen can increase the risk of Cyclosporine nephrotoxicity.

• Antacids and Sucralfate:

  • If Naproxen is administered along with antacids or Sucralfate, delayed absorption of Naproxen is observed.

• Probenecid:

  • Probenecid can increase the plasma levels and half-life of Naproxen.

Use in a Specific Population:

Pregnancy:

Naproxen should not be given to a female during the third trimester of pregnancy as it can induce the premature closure of the ductus arteriosus in the fetus. During the animal studies, it was observed that Naproxen could inhibit prostaglandin secretion, delay parturition, and increase the risk of stillbirth.

Lactating Females:

Naproxen anions have been found in the milk of lactating females, so the risks and benefits of the drug must be considered before administering it.

Pediatric Population:

Insufficient information is available regarding the efficacy and safety of Naproxen in children.

Geriatric Patients:

Studies report that geriatric patients are at a higher risk of adverse reactions associated with NSAIDs than young patients. Hence the drug must be cautiously administered in elderly patients with hepatic or renal dysfunction.

Clinical Trial:

Double-blind, randomized trials were done in patients with rheumatoid arthritis and osteoarthritis to test the safety, efficacy, and duration of the onset of Naproxen. The trial results demonstrated the clinical effectiveness of the drug within a week. Studies also report that Naproxen shows its analgesic action within 30 minutes in patients having pain after oral surgery.