Skelan Forte

Naproxen sodium + Paracetamol (Skelan Forte) 275 mg/325 mg Film-Coated Tablet is a powder-blue, capsule-shaped, film-coated tablet, plain on both sides.
Each film-coated tablet contains: Naproxen sodium 275 mg, Paracetamol 325 mg.

Pharmacology: Pharmacodynamics: Naproxen sodium: Naproxen sodium is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activity by inhibiting cyclooxygenase (COX)-1 and COX-2 isoenzymes resulting in inhibition of prostaglandin synthesis. Pain relief with naproxen sodium usually begins within 30 minutes compared with one hour for plain naproxen.
Paracetamol: Paracetamol exhibits analgesic and antipyretic activity by inhibiting prostaglandin synthesis. It produces analgesia by elevating the pain threshold and antipyresis through its action on the hypothalamic heat regulating center. In therapeutic doses, the analgesic and antipyretic action of paracetamol is comparable to that of aspirin. Paracetamol does not adversely affect platelet function and hemostasis.
Pharmacokinetics: Naproxen sodium: Naproxen and naproxen sodium are readily absorbed from the gastrointestinal (GI) tract. Naproxen sodium is more rapidly absorbed with peak plasma concentrations occurring about one to two hours after oral administration, compared with two to four hours for naproxen. The oral bioavailability of Naproxen sodium is 95%. The rate but not the extent of absorption is decreased when naproxen or naproxen sodium is taken with food.
Naproxen has a volume of distribution of 0.16 L/kg and is more than 99% plasma protein bound. Naproxen plasma concentrations increase proportionately with doses up to 500 mg daily. Increased clearance due to saturation of plasma proteins is seen at higher doses. Naproxen diffuses into synovial fluid, crosses the placenta and is also distributed in small amounts into breast milk. Naproxen's plasma half-life is about 13 hours.
Naproxen is extensively metabolized in the liver, with about 95% of a dose excreted in the urine as naproxen and 6-desmethylnaproxen and their conjugates; less than 5% of a dose is excreted in the feces.
Paracetamol: Paracetamol is rapidly and almost completely absorbed from the GI tract. After oral administration, peak plasma concentrations of paracetamol are attained within 10 to 60 minutes. After 8 hours, only small amounts of the drug are detectable in plasma.
Paracetamol is rapidly and uniformly distributed into most body tissues, except fat. About 10 to 25% of paracetamol in the blood is bound to plasma proteins. Paracetamol has a plasma half-life of 1.25 to 3 hours. It is also metabolized by microsomal enzyme systems in the liver. About 80 to 85% of paracetamol undergoes conjugation predominantly with glucuronic acid and to a lesser extent, with sulfuric acid.
Paracetamol is excreted in the urine mainly as glucuronide with small amounts of sulfate, mercaptate, and unchanged drug. About 85% of the paracetamol dose is excreted as free and conjugated paracetamol within 24 hours after oral administration.
Special Populations: Elderly: Studies demonstrated that the total plasma concentration of naproxen in the elderly is unchanged. However, its unbound plasma fraction is elevated. The clinical significance of this pharmacokinetic alteration is unclear, but it is possible that the increased free naproxen concentration could be related with the increased incidence of adverse events per administered dosage in some elderly patients.
Renal Impairment: Elimination of naproxen sodium is reduced in patients with severe renal impairment. Accumulation of naproxen metabolites and paracetamol conjugates may occur in patients with moderate to severe renal impairment. In addition, severe renal failure reduces the binding of naproxen sodium to serum proteins, resulting to its increased metabolism and volume of distribution in these patients.
Hepatic Impairment: The pharmacokinetics of naproxen sodium in patients with hepatic insufficiency has not been determined. However, chronic alcoholic liver disease or other disease with decreased or abnormal plasma albumin reduce the total plasma levels of naproxen and increase the fraction of unbound naproxen.
The plasma half-life of paracetamol may be prolonged in patients with severe acute and decompensated liver disease.
Bioavailability Study: Naproxen sodium 275 mg + paracetamol 325 mg fixed-dose combination (FDC) tablet was administered in adults under fasting conditions.
Naproxen sodium reached its maximum plasma concentrations (Cmax=58.319 ± 11.4052 mcg/mL) at 0.942 ± 0.6564 hours (Tmax). The total area under the curve from blood level profile from time 0 to 48 hours (AUC0-48h) of naproxen sodium was 783.014 ± 93.5304 mcg·h/mL, while the total area under the plasma concentration curve from time 0 to time infinity (AUC0-∞) was 912.529 ± 122.6362 mcg·h/mL. The mean elimination half-life of naproxen sodium was 17.582 ± 2.3428 hours, and the elimination rate constant was 0.04 ± 0.0052 hr^-1.
Paracetamol attained its Cmax (4.695 ± 1.0018 mcg/mL) at 0.875 ± 0.4361 hours. Its AUC0-48h and AUC0-∞ were 18.477 ± 3.6618 mcg·h/mL and 19.211 ± 3.7612 mcg·h/mL, respectively. The mean elimination half-life of paracetamol was 4.862 ± 1.9968 hours, and the elimination rate constant was 0.169 ± 0.0751 hr^-1.

For the relief of mild to moderate pain and inflammation including headache, migraine, backache, muscular aches, menstrual cramps, minor arthritis pain, toothache, and pain associated with the common cold and flu.
For fever reduction.

The lowest effective dose of naproxen sodium + paracetamol should be used for the shortest possible time consistent with individual patient treatment goals. Patients should be instructed to take this medicine with or after meals with a full glass of water with each dose.
Adults 18 to 65 years of age: Orally, 1 tablet every 8 to 12 hours, as needed, or as prescribed by a doctor.
Special Population: Elderly (65 years and older): Recommended dose: Orally, 1 tablet every 12 hours, or as prescribed by a doctor.
Naproxen sodium + paracetamol should be used in these patients with the shortest duration of use. Patients should be closely supervised for the incidence of adverse events.
Patients with Hepatic and/or Renal Impairment: Naproxen sodium + paracetamol should be used with caution in patients with renal or hepatic impairment (see Precautions).

Naproxen sodium: Symptoms of naproxen overdosage may include headache, lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation, diarrhea, and vomiting; these symptoms have been generally reversible with supportive care. Gastrointestinal bleeding may also occur. Hypertension, respiratory depression, or coma are rarely reported. Acute renal failure and liver damage are possible in significant overdosage. Anaphylactoid reactions were reported with ingestion of therapeutic doses, and may also occur following an overdose. Since high levels of naproxen sodium may be rapidly absorbed, high and early blood levels should be expected. Convulsions, which may or may not be drug-related, have also been reported.
Manage overdosage by symptomatic and supportive care. Patients seen within 4 hours of ingestion may be treated with emesis, gastric lavage, and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg body weight in children) and/or osmotic cathartic. For patients who are comatose, having seizures, or lacks the gag reflex, an endotracheal tube with inflated cuff may be needed during gastric lavage to prevent aspiration of gastric contents. Hemodialysis, forced diuresis, alkalinization of urine, or hemoperfusion may not be beneficial because naproxen sodium is highly protein bound.
Paracetamol: Overdosage of paracetamol usually involves four phases with the following signs and symptoms: Anorexia, nausea, vomiting, malaise, and diaphoresis.
Resolution of Phase I symptoms, and the manifestations of the following: right upper quadrant abdominal pain or tenderness, liver enlargement which may be characterized by abdominal discomfort of "feeling full", elevated bilirubin and liver enzyme concentrations, prolongation of prothrombin time, and occasionally oliguria.
Anorexia, nausea, vomiting, and malaise recur usually three to five days after initial symptom onset; and signs of liver failure (e.g., jaundice, hypoglycemia, coagulopathy, encephalopathy) and possibly kidney failure and cardiomyopathy.
Recovery or progression to fatal complete liver failure.
Immediate medical management is required in the event of an overdose, even if the patient is asymptomatic. Patients should be admitted to hospital for full supportive measures to be instituted. Activated charcoal may be used to reduce GI absorption and should be administered within 1 hour of paracetamol ingestion. Plasma or serum paracetamol assay should be obtained as soon as possible, but no sooner than 4 hours following oral ingestion. As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against time since oral ingestion on a nomogram (Rumack-Matthew). A level ≤150 mcg/mL and absence of toxic symptoms indicate that hepatotoxicity is very unlikely. Higher levels indicate possible hepatotoxicity. For acute poisoning, oral or intravenous acetylcysteine is given if hepatotoxicity is likely based on paracetamol dose or serum level. Acetylcysteine is most effective if given within 8 hours of paracetamol ingestion. If degree of toxicity is uncertain, acetylcysteine should be given until toxicity is ruled out. Liver function tests should be obtained initially and repeated at 24-hour intervals.
Liver failure is treated supportively. Patients with fulminant hepatic failure may require liver transplantation.

Hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen sodium, aspirin, NSAIDs, paracetamol or to any component in the product.
Patients who are diagnosed with asthma, urticaria, or other allergic reactions after taking aspirin or other NSAIDs (see Precautions).
Patients with active peptic/duodenal/GI ulcers, bleeding or perforation related to previous NSAID therapy.
Patients with active recurrent peptic ulcer/hemorrhage (two or more distinct episodes of proven ulceration or bleeding) unrelated to previous NSAID therapy.
Patients with cerebrovascular bleeding or other bleeding disorders.
Patients with inflammatory bowel disease, chronic dyspepsia, congestive gastritis, or atrophic gastritis.
Patients with known hyperkalemia.
Patients with severe uncontrolled cardiac failure (see Precautions).
Patients with severe liver impairment or severe active liver disease.
Patients with severe renal impairment (creatinine clearance <30 mL/min) or deteriorating renal disease.
During the last trimester of pregnancy.
Breastfeeding women.
In the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

Naproxen sodium: Risk of Serious Cardiovascular and Gastrointestinal Adverse Events: As with all NSAIDs, naproxen sodium may increase the risk of serious cardiovascular (CV) thrombotic events, such as myocardial infarction and stroke, which can be fatal and may lead to hospitalization or death. The risk may occur early in treatment and may increase with dose and duration of use. Patients with pre-existing CV disease or risk factors for CV disease may be at greater risk (see Precautions). NSAIDs, including naproxen sodium, cause an increased risk of serious GI adverse events (e.g., bleeding, ulceration, perforation) which can be life-threatening. These events may occur at any time during NSAID therapy and even without warning symptoms. Elderly patients and those with known history of peptic ulcer disease and/or GI bleeding have a greater risk for those serious GI events (see Precautions).

Naproxen sodium: Cardiovascular and Thrombotic Effects: As with all NSAIDs, naproxen sodium may increase the risk of serious cardiovascular (CV) thrombotic events, such as myocardial infarction and stroke, which can be fatal and may lead to hospitalization or death. The risk may occur early in treatment and may increase with dose and duration of use. Patients with pre-existing CV disease or risk factors for CV disease may be at greater risk.
Naproxen sodium + paracetamol should be prescribed after careful considerations in patients with established ischemic heart disease, congestive heart failure, coronary heart disease, peripheral arterial disease, transient ischemic attacks, and amaurosis fugax. To minimize the potential risk for CV adverse event, the lowest effective dose should be administered with the shortest duration possible. Similar consideration must be made prior to starting long-term treatment of patients with risk factors for CV events (e.g., dyslipidemia/hyperlipidemia, diabetes mellitus, smoking). Both physicians and patients should be vigilant for the occurrence of these adverse events, even in the absence of previous CV symptoms. Patients should be informed of the signs and symptoms of serious cardiovascular toxicity (e.g., chest pain, dyspnea, slurring of speech) and to immediately seek medical attention if such signs or symptoms occur. An alternative treatment for high-risk patients should also be considered.
Hypertension: NSAIDs, such as naproxen sodium, may either result to possible onset of new hypertension or may worsen pre-existing hypertension. Response to antihypertensives may be impaired in patients taking NSAIDs (see Interactions). Naproxen sodium + paracetamol should be used with caution in hypertensive patients. Regular monitoring of blood pressure in the initiation and during NSAID therapy is recommended. Discontinuation of NSAID therapy must be considered if hypertension develops.
Congestive Heart Failure and Edema: Treatment with NSAIDs may cause fluid retention, edema (including peripheral edema), and heart failure. The use of naproxen sodium may also lessen the therapeutic effects of drugs used to manage these medical conditions (see Interactions). Naproxen sodium + paracetamol should be administered with caution in patients at risk for congestive heart failure (e.g., post-myocardial infarction), or those with fluid retention or mild to moderate heart failure, especially in those patients with questionable or compromised cardiac function. Naproxen sodium + paracetamol should not be administered in patients with severe heart failure, unless benefits are expected to outweigh the risks of worsening heart failure. Patients should be instructed to immediately inform their physicians if they experience symptoms of heart failure (e.g., dyspnea, unexplained weight gain, or edema). It is important to consider the sodium content of naproxen sodium (each naproxen sodium 275 mg contains 25 mg sodium) in patients whose overall sodium intake must be severely restricted.
Gastrointestinal Effects: Adverse reactions of naproxen sodium mainly affect the GI tract. Some of these GI effects (e.g., inflammation, bleeding, ulceration, and perforation of the upper or lower GI tract) may be serious or even fatal. These adverse events may occur any time during NSAID therapy, with or even without warning symptoms.
Short-term NSAID therapy has potential risk: upper GI ulcers and gross bleeding or perforation occurred in about 1% of patients treated for three to six months. These trends persist with longer duration of therapy, as approximately 2 to 4% in patients treated with NSAIDs for one year experienced GI events.
Naproxen sodium + paracetamol should be prescribed with extreme caution in those with history of ulcer disease or GI bleeding, since these patients have greater than 10-fold increased risk for developing GI bleeding compared with patients with neither of these risk factors. Other risk factors for serious GI bleeding include the following: prolonged NSAID therapy, poor general health status, advanced liver disease and/or coagulopathy, advanced age (>60 years old), smoking, alcoholism (especially those consuming three or more alcoholic beverages per day), or concomitant use of oral corticosteroids, anticoagulants, selective serotonin reuptake inhibitors (SSRIs) or other NSAIDs. Caution should also be exercised in administering naproxen sodium + paracetamol in patients with history of inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease), as these conditions may be exacerbated.
The lowest effective dose should be used for the shortest possible duration to minimize the potential risk for any adverse GI event. Administration of more than one NSAID at a time should be avoided. To reduce the incidence of GI events, combination therapy with gastroprotective agents (e.g., proton pump inhibitors) may be considered for patients at high risk of developing these adverse events and for those requiring concomitant treatments with aspirin or other drugs that induce gastrointestinal toxicity. Since only one in five patients who develop a serious upper GI adverse reaction is symptomatic, physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. Patients, especially the elderly and those with history of GI events, should also be instructed to withdraw treatment with naproxen sodium + paracetamol, promptly report any unusual abdominal symptoms (particularly GI bleeding), and seek emergency medical attention once they have experienced these symptoms. Additional evaluation and treatment or measures should be promptly initiated if a serious GI adverse event is suspected. Discontinuation of the NSAID should be considered until a serious GI adverse event is ruled out. Alternate therapies other than NSAIDs should be considered especially for high-risk patients.
Renal Effects and Hyperkalemia: Long-term administration of NSAIDs has resulted to renal papillary necrosis and other renal effects (e.g., acute interstitial nephritis, glomerulonephritis, low grade proteinuria, and occasionally, nephrotic syndrome). Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion and glomerular perfusion rate (GFR). In these patients NSAIDs may cause a dose-dependent inhibition of prostaglandin synthesis and on renal perfusion, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are the elderly, those with dehydration, hypovolemia, heart failure, liver dysfunction, those on salt-restricted diet, and those taking angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and diuretics (see Interactions). Discontinuation of treatment with NSAIDs is usually followed by recovery to pre-treatment states.
Volume status of dehydrated or hypovolemic patients should be corrected prior to initiating treatment with naproxen sodium + paracetamol. Assessment of renal function should also be performed before and during treatment, especially in patients with compromised renal blood flow (i.e., elderly patients; patients on sodium restriction, diuretics), renal or hepatic impairment, heart failure, dehydration or hypovolemia.
NSAIDs can increase the risk of hyperkalemia even in patients without renal impairment, but particularly in patients with diabetes mellitus, advanced age, or those on concomitant therapy with antihypertensives or ciclosporin (see Interactions). In patients with normal renal function, these renal effects are attributed to a hyporeninemic-hypoaldosteronism state. Serum levels of electrolytes should be periodically monitored during treatment with naproxen sodium.
Hypersensitivity Reactions: Severe, rarely fatal, anaphylactic/anaphylactoid reactions may occur even in patients without known prior exposure to naproxen sodium or in aspirin-sensitive patients.
A subset of patients with asthma may have aspirin-sensitive asthma, whose symptoms include chronic bronchitis worsened by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin or to other NSAIDs. Since cross-reactivity between aspirin and NSAIDs is possible, naproxen sodium is contraindicated in aspirin-sensitive patients. Naproxen sodium + paracetamol should be administered with caution in patients suffering from, or with a previous history of bronchial asthma or allergic disease. These patients should be monitored closely for changes in the signs and symptoms of asthma.
Patients should be instructed to promptly withdraw treatment and to seek emergency help immediately at the first appearance of signs and symptoms of anaphylactoid reaction (e.g., difficulty in breathing, swelling of the face or throat, skin rash, blisters, fever).
Serious Skin Reactions: The use of NSAIDs has been rarely associated with serious skin reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), exfoliative dermatitis, and erythema multiforme. Serious skin events associated with NSAIDs are reversible upon drug discontinuation, may occur without warning, and may be fatal. Moreover, these reactions are idiosyncratic and independent of dose or duration of use.
Patients have the highest risk for these serious skin reactions during the early phase of NSAID therapy. Patients should be instructed to discontinue treatment with naproxen sodium + paracetamol upon the first appearance of manifestations of any skin or hypersensitivity reactions, and to contact their physician for assessment and advice. If symptoms of pseudoporphyria occur (e.g., skin becomes delicate, blistering), treatment should be withdrawn and the patient should be carefully monitored.
Hepatic/Biliary/Pancreatic Effects: Borderline elevations of one or more liver enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase] may occur up to 15% of patients taking NSAIDs. Significant elevations (three times the upper limit of normal) of ALT or AST were observed in less than 1% of patients in controlled clinical trials. These alterations in liver function test may be transient, unchanged, or may progress with continued therapy. Furthermore, severe hepatic reactions including jaundice and fatal cases of hepatitis, fulminant hepatitis, liver necrosis, and hepatic failure have been reported with the use of NSAIDs. These hepatic abnormalities may be caused by hypersensitivity rather than direct hepatotoxicity.
Serum transaminase and bilirubin levels should be regularly monitored during therapy with naproxen sodium + paracetamol. Physicians should inform their patients about the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, abdominal tenderness in the right upper quadrant, and flu-like symptoms). Treatment with NSAIDs should be discontinued if clinical symptoms and/or signs of liver dysfunction occurred, if abnormal liver function test is persistent or worsening, or if systemic manifestations appear (e.g., eosinophilia, associated with rash, etc.). Patients should be clinically evaluated for evidence of the development of a more severe hepatic reaction during treatment.
Hematologic Effects: In some patients, NSAIDs inhibit prostaglandin biosynthesis and platelet aggregation, which may lead to prolonged bleeding times. However, compared with aspirin, the effect of naproxen on platelet function is quantitatively lesser or of shorter duration, and is reversible. Anemia due to fluid retention, occult or gross GI blood loss, or an incompletely described effect on erythropoiesis, may also be observed in some patients receiving NSAIDs.
Patients who have coagulation or platelet disorders, or are receiving drug therapy that interferes with hemostasis (see Interactions) may have an increased risk of bleeding and must be carefully observed during treatment with naproxen sodium + paracetamol. Hematocrit or hemoglobin levels of patients on long-term treatment with NSAID should be checked if they exhibit any signs or symptoms of anemia or blood loss, while patients with initial hemoglobin values of ≤10 grams should have their hemoglobin values checked regularly. Complete blood counts should also be checked on long-term treatment with naproxen sodium + paracetamol to monitor the development of blood dyscrasias.
Effects on the Endocrine System: Naproxen sodium cannot be a substitute for a corticosteroid, nor can it be used to treat corticosteroid insufficiency. If a decision is made to discontinue corticosteroids, it should be gradually tapered to avoid the exacerbation of the disease being treated (see Interactions).
Ophthalmologic Effects: Blurred and/or diminished vision has been reported with the use of NSAIDs. Papillitis, retrobulbar optic neuritis, and papilledema rarely occurred in NSAID users; however, causality cannot be established. Regular ophthalmologic evaluation should be carried out in patients in a long-term treatment with naproxen sodium + paracetamol. Treatment with naproxen sodium + paracetamol should be discontinued once these symptoms develop, and an ophthalmologic examination should be performed.
Genitourinary Effects: Some NSAIDs are associated with genitourinary effects such as hematuria, cystitis, and other persistent urinary symptoms (e.g., bladder pain, dysuria, urinary frequency). These symptoms may manifest any time during NSAID therapy. Treatment with naproxen sodium + paracetamol should be discontinued if these urinary symptoms occur and if there is no other explanation for the appearance of these symptoms. This should be performed prior to any urological investigations or treatments.
Infections and Use in Patients with Autoimmune Disease: The antipyretic, analgesic, and the anti-inflammatory properties of naproxen sodium may mask signs and symptoms of an underlying infectious disease, thus affecting the diagnosis or detection of any infections. Symptoms of aseptic meningitis (e.g., stiff neck, severe headaches, nausea, vomiting, fever or clouding of consciousness) have been rarely observed with the use of some NSAIDs. Patients with autoimmune disorders such systemic lupus erythematosus, mixed connective tissue diseases must be vigilantly monitored, since they are more susceptible to the risk of aseptic meningitis.
Effects on Reproductive System and Fertility: Naproxen sodium, as with any cyclooxygenase/prostaglandin synthesis inhibitor, may delay or prevent the rupture of ovarian follicles and may result to reversible infertility. Therefore, its use in women attempting to conceive is not recommended. Withdrawal of use should also be considered in women who have difficulties in conceiving, or who are undergoing investigation for infertility.
Paracetamol: Sensitivity and Serious Skin Reactions: Hypersensitivity and anaphylaxis associated with the use of paracetamol have been reported. Moreover, there have been rare reports of serious (and may be fatal) skin reactions associated with the use of paracetamol, such as acute generalized exanthematous pustulosis (AGEP), SJS, and TEN. Patients should be informed to discontinue treatment immediately at the first appearance of clinical signs of hypersensitivity (e.g., swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, and pruritus) or of other signs of these serious skin reactions (e.g., urticaria, pruritus, pruritic maculopapular rash, periorbital edema) and to seek immediate medical attention once these reactions occurred.
Hepatic Effects: Since they are at greater risk of having impaired renal function due to prostaglandin inhibition, naproxen sodium + paracetamol should be used with caution in patients with hepatic impairment (see Patient with Hepatic Impairment as follows).
Patients who take more than three alcoholic drinks a day (see Interactions), those who take more than one paracetamol-containing medicine, and those who exceed the recommended daily dosage (≤4 g per day) of paracetamol are at higher risk of developing severe hepatotoxicity. Hepatic dysfunction or failure due to paracetamol have been reported in patients who have depleted glutathione levels, such as those with severe malnourishment, anorexia, or low body mass index.
Hematologic Effects: Prolonged administration of large doses of paracetamol is associated with blood dyscrasias such as thrombocytopenia, leukopenia, and pancytopenia. Moreover, neutropenia, anemia, and thrombocytopenia purpura have occurred during paracetamol intake. Agranulocytosis has been rarely reported.
Paracetamol should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD).
Metabolic Effects: The risk of metabolic acidosis with the use of paracetamol is increased in patients with low glutathione levels (e.g., patients with sepsis).
Antipyretic Effect: The antipyretic and analgesic properties of paracetamol may mask signs and symptoms of an underlying infectious disease, thus affecting the diagnosis or detection of any infections.
General Precautions: Naproxen sodium should not be concomitantly used with other naproxen- or naproxen sodium-containing medicines since they all circulate in the plasma as the naproxen anion. Moreover, this medicine should not be co-administered with other paracetamol-containing preparations to reduce the risk of hepatotoxicity.
Lactose: This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Patients with Renal Impairment: Since naproxen sodium is known to be significantly excreted in the kidneys, it should be administered with caution in patients with impaired renal function. The administration of NSAIDs in patients with impaired renal function (glomerular filtration rate <60 mL/min or 1 mL/sec) may cause a dose-dependent prostaglandin inhibition and decrease in renal blood flow, which may precipitate renal failure. Moreover, serious to fatal renal failure has been reported in patients with impaired renal function following short-term treatment with NSAIDs. Patients should inform their physicians if unexplained weight gain or edema occurs. Discontinuation of therapy with NSAIDs is usually followed by recovery to the pretreatment state, but serious adverse effects may persist. If therapy with naproxen sodium + paracetamol must be initiated, adequate hydration and diuresis of the patient should be ensured, and close monitoring of the renal function is should be performed periodically.
The use of naproxen sodium + paracetamol is contraindicated in patients with severe renal disease (creatinine clearance <30 mL/min) or deteriorating renal disease. Hemodialysis does not reduce the naproxen plasma concentrations due to its high degree of protein binding.
Patients with Hepatic Impairment: As patients with liver dysfunction are at greater risk of having impaired renal function due to prostaglandin inhibition, patients with hepatic impairment or active liver disease should be treated with caution and strict observation, especially if high doses of NSAIDs are required. This population should also have their renal function assessed prior to and during NSAID therapy. Naproxen sodium + paracetamol is contraindicated in patients with severe hepatic impairment or severe acute liver disease. The risk of paracetamol overdose is greater in patients with non-cirrhotic alcoholic liver disease. Moreover, underlying liver disease increases the susceptibility of the patient to paracetamol-related liver damage.
Effects on Ability to Drive and Use Machines: Naproxen sodium may cause adverse events that may impair judgment, thinking, or motor skills (e.g., drowsiness, dizziness, visual disturbances, vertigo, tinnitus, hearing loss, insomnia or depression). Thus, patients should be cautioned about carrying out activities that require mental alertness and physical coordination, such as operating hazardous machinery and driving motor vehicles, while taking naproxen sodium + paracetamol.
Use in Children: The safety and efficacy of naproxen sodium + paracetamol is not yet established in patients younger than 18 years of age. Thus, its use in this population is not recommended.
Use in the Elderly: Elderly patients may have greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease or drug therapy, and have the potential for greater susceptibility to adverse events, such as gastrointestinal (e.g., GI bleeding and ulceration) and renal effects. Since the unbound plasma fraction of naproxen sodium is greater in elderly patients than in younger adults, the lowest dose should be used for the shortest possible time. Elderly patients should be monitored for adverse effects (especially for GI effects) and renal function during treatment.

Pregnancy: Pregnancy Category C. Naproxen sodium crosses the placenta. Due to its property to inhibit prostaglandin synthesis, naproxen use during early pregnancy may increase the risk of miscarriage, cleft palate, gastroschisis, and cardiac malformation to the fetus.
Naproxen sodium use in the last trimester of pregnancy to delay parturition is not recommended. It exposes the fetus to cardiopulmonary toxicity (i.e., patent ductus arteriosus, risk of premature closure of the ductus arteriosus and severe hypoxemia due to pulmonary hypertension), necrotizing enterocolitis, abnormal prostaglandin E levels, intracranial hemorrhage, GI bleeding, and renal dysfunction, which may progress to renal failure with oligo-hydroamniosis. The bleeding time of both the mother and the fetus may possibly be prolonged at the end of pregnancy due to platelet dysfunction. Therefore, the use of naproxen sodium in the third trimester of pregnancy is contraindicated.
Paracetamol crosses the placenta. Epidemiologic data on the use of oral paracetamol in pregnant women have demonstrated no increased risk of major congenital malformations in infants exposed in utero.
Since no studies in pregnant women and animal reproduction studies have been conducted with this fixed-dose combination, naproxen sodium + paracetamol should only be used during pregnancy only when clearly needed.
Lactation: Both naproxen sodium and paracetamol are distributed into the milk of lactating women. Naproxen sodium may produce adverse effects to the breastfed infant due to prostaglandin inhibition. Thus, the use of naproxen sodium + paracetamol should be avoided in breastfeeding women.

Naproxen sodium: The most commonly reported adverse reactions associated with naproxen sodium are gastrointestinal (e.g., heartburn, constipation, abdominal pain, nausea), of which peptic ulcer, with or without bleeding, is the most severe. Headache, dizziness, drowsiness, pruritus, ecchymoses, skin eruptions, and tinnitus are also frequently reported.
Infections and infestations: Infections, sepsis.
Blood and lymphatic system disorders: Agranulocytosis, anemia, aplastic anemia, coagulopathy, eosinophilia, granulocytopenia, hemolytic anemia, immune thrombocytopenic purpura, leukopenia, lymphadenopathy, pancytopenia, thrombocytopenia.
Immune system disorders: Anaphylactic reaction, anaphylactoid reaction, angioneurotic edema, bronchospasm, systemic lupus erythematosus.
Metabolism and nutrition disorders: Anorexia, changes in appetite, decreased appetite, edema, fluid retention, hyperglycemia, hyperkalemia, hypoglycemia, peripheral edema.
Psychiatric disorders: Abnormal dreams, anxiety, confusion, depression, disorientation, disturbance in attention, euphoria, hallucinations, insomnia, sleep disorders, somnolence.
Nervous system disorders: Aseptic meningitis, ataxia, cognitive dysfunction (e.g., difficulty in calculations), coma, convulsion, dizziness, dysarthria, exacerbation of Parkinson's disease, lightheadedness, loss of short-term memory, myasthenia, nervousness, paresthesia, peripheral neuropathy, seizures, tremor, vertigo.
Eye disorders: Blurred vision, conjunctivitis, corneal opacity, exacerbation of glaucoma, keratopathy, papilledema, papillitis, retrobulbar optic neuritis, visual impairment.
Ear and labyrinth disorders: Hearing disturbances, hearing impairment.
Cardiac disorders: Arrhythmia, cardiac failure, chest discomfort, chest pain, congestive heart failure, myocardial infarction, palpitations, tachycardia.
Vascular disorders: Cerebrovascular accident, hypersensitivity vasculitis, hypertension, hypotension, stroke, syncope, vasculitis, worsening of hypertension.
Respiratory, thoracic, and mediastinal disorders: Aggravated asthma, asthma, dyspnea, eosinophilic pneumonia, pneumonia, pulmonary edema, respiratory depression, rhinorrhea, wheezing.
Gastrointestinal disorders: Abdominal discomfort, aggravated Crohn's disease, aggravated ulcerative colitis, aphthous stomatitis, colitis, diarrhea, diverticulitis, dry mouth, dyspepsia, eosinophilic colitis, epigastric distress, eructation, esophageal ulcer, esophagitis, flatulence, gastritis, gastrointestinal hemorrhage, gastrointestinal inflammation, gastrointestinal obstruction, gastrointestinal perforation, gastrointestinal ulceration (gastric/duodenal/nonpeptic), glossitis, hematemesis, melena, oropharyngeal pain, pancreatitis, peptic ulcerations (with or without bleeding), rectal hemorrhage, salivary gland enlargement, stomatitis, throat irritation, ulcerative stomatitis, vomiting.
Hepatic and hepatobiliary disorder: Cholestatic jaundice, cholestasis, fulminant hepatitis, hepatic cirrhosis, hepatitis, jaundice, liver failure.
Skin and subcutaneous tissue disorders: Alopecia, blister, bullous dermatitis, epidermolysis bullosa, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, facial scars, fixed drug eruption, lichen planus, photodermatosis, photosensitive dermatitis, photosensitivity reaction, pseudoporphyria, purpura, pustular reaction, rash, skin fragility, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.
Musculoskeletal and connective tissue disorders: Muscle spasms, muscle weakness, musculoskeletal stiffness, myalgia, stiff neck.
Renal and urinary disorders: Acute renal failure, cystitis, dysuria, glomerular nephritis, hematuria, interstitial nephritis, nephritic syndrome, nephritis, nephrotic syndrome, nephropathy, oliguria, pollakiuria, polyuria, proteinuria, renal disease, renal failure, renal insufficiency, renal papillary necrosis, renal tubular necrosis.
Reproductive system and breast disorders: Infertility [female], menstrual disorder.
General disorders and administration site conditions: Asthenia, chills, death, fatigue, fever, hypothermia, irritability, malaise, pyrexia, sweating, thirst, weakness.
Investigations: Abnormal liver function tests, abnormal renal function, changes in weight (i.e., weight gain), decreased creatinine clearance, elevated liver enzymes, increased alkaline phosphatase (ALP), increased blood pressure, increased blood urea nitrogen, increased bilirubin levels, increased serum creatinine, prolonged bleeding times.
Paracetamol: Paracetamol, when taken within the recommended dose and duration of treatment, has low incidence of side effects. The most common side effects are constipation, headache, insomnia, nausea, and vomiting.
Infections and infestations: Infections.
Blood and lymphatic system disorders: Agranulocytosis, anemia, leukopenia, methemoglobinemia, neutropenia, pancytopenia, thrombocytopenia, thrombocytopenic purpura.
Immune system disorders: Angioedema, anaphylactoid reactions, anaphylaxis, asthma, bronchospasm, laryngeal edema, periorbital edema, swelling of the face, mouth, and throat.
Metabolism and nutrition disorders: Anorexia, hyperammonemia, hyperchloremia, hyperuricemia, metabolic acidosis, pyroglutamic aciduria, sudden weight loss.
Ear and labyrinth disorders: Hearing loss.
Vascular disorders: Hemorrhage, hypertension, hypotension.
Respiratory, thoracic and mediastinal disorders: Dyspnea, respiratory distress, rhinorrhea, wheezing.
Gastrointestinal disorders: Gastrointestinal disturbances, mouth ulceration.
Hepatobiliary disorders: Acute liver failure, hepatic dysfunction, hepatotoxicity, jaundice.
Skin and subcutaneous tissue disorder: Acute generalized exanthematous pustulosis, blister, contusion, erythema, pruritus, rash (pruritic maculopapular), skin exfoliation, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.
Renal and urinary disorders: Nephropathy.
Investigations: Decreased serum bicarbonate, decreased serum calcium, decreased serum sodium, increased alanine aminotransferase, increased aspartate aminotransferase (AST), increased serum glucose.

Naproxen sodium: Albumin-bound drugs (e.g., hydantoins, sulfonamides, sulfonylureas, coumarin-type anticoagulants, aspirin, other NSAIDs): Naproxen is highly bound to plasma albumin. Theoretically, it can be displaced from binding sites or it can displace other protein-bound drugs from binding sites. Thus, patients who are receiving naproxen concomitantly with any of these drugs should be carefully monitored for possible dosage adjustment and adverse effects.
Anticoagulants/Thrombolytic agents (e.g., warfarin, heparin, streptokinase): The concomitant use of warfarin and NSAIDs synergistically increases the risk of serious GI bleeding compared with either drug used alone. Administration of naproxen with warfarin results in a slight increase in free warfarin in serum, but does not affect the hypoprothrombinemic effect of warfarin. Caution should be exercised when giving naproxen to patients taking any anticoagulant or thrombolytic agent. Close monitoring of international normalized ratio (INR) should also be conducted.
ACE inhibitors (e.g., captopril, fosinopril, imidapril, enalapril), ARBs (e.g., losartan, telmisartan), and beta-blockers: NSAIDs, such as naproxen sodium, may reduce the anti-hypertensive effects of ACE inhibitors, ARBs, and beta-blockers. Moreover, naproxen may also increase the risk of renal dysfunction (i.e., acute renal failure) in patients taking ACE inhibitors and ARBs, particularly in elderly patients, volume-depleted patients (including those on diuretic therapy), or those with pre-existing poor renal function. The risk for acute renal failure and hyperkalemia may also be induced with the coadministration of naproxen with ACE inhibitors and ARBs.
Blood pressure, serum electrolyte levels, and renal function should be closely monitored, as the blood pressure may significantly increase during concurrent use. Patients should be adequately hydrated, and renal function should be assessed at the beginning and periodically during the concomitant treatment.
Anti-platelet Agents (e.g., aspirin, clopidogrel, cilostazol, dipyridamole): The coadministration of anti-platelet agents and naproxen in patients who have coagulation disorders may increase the risk of bleeding and may prolong bleeding time. The benefit of coadministration of naproxen with these drugs should be weighed against the risk.
Aspirin: The concomitant use of naproxen with aspirin is not recommended. Aside of the little to no increase in efficacy, the concomitant therapy may result to additive adverse reactions and may increase the risk for serious GI events. Moreover, naproxen may attenuate the anti-platelet property of aspirin.
There is no consistent evidence that low-dose aspirin lessens the increased risk of serious cardiovascular events associated with NSAIDs. Contrarily, some evidences demonstrated that the use of NSAIDs may significantly diminish the cardioprotective effects of aspirin.
Aspirin taken concomitantly with naproxen may decrease protein binding of naproxen, but clearance of free (unbound) naproxen does not seem to be altered.
The clinical importance of this pharmacokinetic interaction has not been established.
Bisphosphonates: Coadministration of NSAIDs and bisphosphonates may increase the risk of gastric mucosal damage.
Cholestyramine: Cholestyramine can delay the rate (but not the extent) of naproxen absorption. Naproxen sodium should be taken at least one hour prior, or four to six hours following cholestyramine administration.
Corticosteroids: Caution is advised when corticosteroids are given together with NSAIDs because of the increased risk of GI ulceration or bleeding, especially in patients older than 65 years of age.
If dosage of corticosteroid is to be reduced during naproxen therapy, it should be done gradually. Patients must be closely monitored for any adverse effects, including adrenal insufficiency or symptomatic exacerbation of the condition being treated.
Ciclosporin, tacrolimus: Caution is advised when ciclosporin or tacrolimus is given together with an NSAID because of the increased risk of nephrotoxicity.
Digoxin: NSAIDs may increase plasma digoxin concentrations and may prolong the half-life of digoxin, which may result in digitalis toxicity. NSAIDs may also exacerbate cardiac failure and reduce the glomerular filtration rate (GFR) in patients taking digoxin. Increased monitoring of serum levels and dosage adjustments of the cardiac glycosides may be required during and after concurrent NSAID therapy.
Diuretics: Naproxen can reduce the natriuretic effect of furosemide or thiazide diuretics. This interaction has been the result of the inhibition of renal prostaglandin synthesis. Moreover, the use of NSAIDs with diuretics may increase the risk for acute renal failure and hyperkalemia. Patients should be monitored closely for blood pressure and renal function (including serum electrolytes) to assure diuretic efficacy during concomitant therapy with NSAIDs.
Drugs affecting gastric pH [e.g., antacids (magnesium oxide, aluminum hydroxide, sodium bicarbonate), sucralfate]: Concomitant administration of naproxen with antacids or sucralfate may result to a delay in the absorption rate of naproxen.
Sodium bicarbonate increases the aqueous solubility of naproxen sodium, resulting to enhanced absorption rate of naproxen sodium.
H2 receptor antagonists: It has been demonstrated that the coadministration of cimetidine, ranitidine, or famotidine reduced the half-life of naproxen by approximately 50%. This interaction does not appear to be clinically important. However, since H2 antagonists may protect the gastric mucosa from the irritant effects of NSAIDs, the concurrent use of these drugs with naproxen sodium may be beneficial.
Lithium: NSAIDs may elevate plasma lithium concentrations by about 15% and reduce renal lithium clearance by approximately 20%, leading to an increased risk of lithium toxicity due to the inhibition of renal prostaglandin synthesis. Patients should be closely observed for signs of lithium toxicity, and monitoring of plasma lithium concentrations should be performed during the initial phases of the concomitant therapy and following dosage modifications. Appropriate lithium dosage adjustment may be required when therapy with naproxen sodium is discontinued.
Methotrexate: Severe and sometimes fatal toxicity has occurred following the concomitant use of NSAIDs with high-dose methotrexate in patients with various malignant neoplasms or rheumatoid arthritis. The mechanism of this interaction is not yet established, but it is suggested that NSAIDs decrease the renal perfusion of methotrexate either by inhibition of renal prostaglandin synthesis or by competing for renal elimination. Thus, caution is advised in the coadministration of naproxen with methotrexate. Patients should be monitored for renal function, full blood counts, and signs of methotrexate toxicity.
Other NSAIDs (e.g., ibuprofen, mefenamic acid, ketorolac, diclofenac): Concomitant use of naproxen with other NSAIDs (including selective COX-2 inhibitors) is not recommended, since it may result to additive adverse reactions and may increase the risk for serious GI events.
Pemetrexed: The use of naproxen sodium with pemetrexed may increase the risk of pemetrexed-associated myelosuppression, nephrotoxicity, and GI toxicity. Patients should be monitored for the signs of increased pemetrexed toxicity.
Probenecid: Probenecid has been suggested to interfere with the metabolism and excretion of naproxen. The mechanism of this interaction involves the marked decrease in urinary excretion of native naproxen and an increase in urinary 6-O-desmethylnaproxen, resulting to increased naproxen anion plasma levels and significantly prolonged plasma half-life (i.e., from 14 hours to 37 hours following a single dose of naproxen 500 mg). Thus, probenecid should be carefully coadministered with naproxen, and patients should be monitored for possible dosage adjustments.
Quinolone antibiotics: Patients taking quinolones together with NSAIDs may have an increased risk of convulsions.
Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, citalopram, sertraline) and serotonin-norepinephrine reuptake inhibitors (SNRIs): An increased risk of GI ulceration and bleeding may occur when naproxen sodium and SSRIs are taken concomitantly. Caution should be exercised in the administration of naproxen during SSRI therapy.
Zidovudine: Since NSAIDs may interfere with the metabolism of zidovudine, the coadministration of these drugs may result to higher zidovudine plasma levels and increased risk of zidovudine toxicity, especially hematological effects. Dose reduction may be considered.
Paracetamol: Alcohol: The effects of alcohol in the pharmacokinetics of paracetamol are complex. Excessive alcohol consumption may induce hepatic cytochrome enzymes. However, alcohol may also act as a competitive inhibitor in the metabolism of paracetamol. Coadministration of paracetamol with alcohol can increase the risk of paracetamol-induced hepatotoxicity (see Precautions).
Anticonvulsants (e.g., barbiturates, carbamazepine, phenytoin): Some anticonvulsants induce the hepatic microsomal enzymes, resulting to the increased conversion of paracetamol to hepatotoxic metabolites and increasing the risk of paracetamol-induced hepatotoxicity.
Chloramphenicol: The coadministration of paracetamol may increase chloramphenicol concentrations.
Cholestyramine: Cholestyramine, especially if taken within one hour of paracetamol administration, may reduce the absorption of paracetamol.
Domperidone or metoclopramide: The absorption of paracetamol may be accelerated by drugs that increase gastric emptying, such as metoclopramide or domperidone.
Enzyme-inducing agents (e.g., amoxicillin + clavulanic acid, anticoagulants, ethanol, isoniazid, zidovudine): Administering paracetamol with drugs that induce hepatic cytochrome enzymes (especially CYP2E1) may result in an increased level of paracetamol's hepatotoxic metabolites, thus increasing the risk of hepatotoxicity. Caution should be performed in the coadministration of paracetamol with these drugs. Patients receiving these drugs should be instructed to limit their paracetamol intake.
Drugs that decrease gastric emptying: The absorption of paracetamol may be reduced if it is concomitantly administered with drugs that decrease gastric emptying (e.g., propantheline, antidepressants with anticholinergic properties, narcotic analgesics).
Hepatotoxic drugs (e.g., isoniazid): The risk of paracetamol toxicity may be increased in patients taking paracetamol together with other potentially hepatotoxic drugs.
Lamotrigine: Multiple oral doses of paracetamol may reduce the AUC and half-life of lamotrigine. Moreover, paracetamol may also increase the percentage of lamotrigine recovered in the urine.
Oral anticoagulants (e.g., warfarin and other coumarins): Chronic ingestion of large doses of paracetamol may potentiate the anticoagulant effect of warfarin and other coumarin- and indanedione-derivative anticoagulants, which may result in increased risk of bleeding. Prothrombin time (PT) and International Normalized Ratio (INR) must be monitored.
Phenothiazines: Concomitant use of paracetamol with phenothiazines may increase the risk of severe hypothermia.
Probenecid: Probenecid may alter the plasma concentration and excretion of paracetamol.
Interactions with Laboratory Tests: Naproxen sodium: In the determination of bleeding time, it should be kept in mind that naproxen may decrease platelet aggregation and prolong bleeding time.
Naproxen may increase urinary values of 17-ketogenic steroids due to its interaction with the m-dinitrobenzene used in the assay. Discontinue naproxen sodium therapy temporarily for 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Naproxen may interfere with urinary assays of 5-hydroxy indoleacetic acid.
Paracetamol: Paracetamol may yield false-positive test results for urinary 5-hydroxyindoleacetic acid.

Store at temperatures not exceeding 30°C.

Analgesics (Non-Opioid) & Antipyretics / Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

N02BE51 - paracetamol, combinations excl. psycholeptics ; Belongs to the class of anilide preparations. Used to relieve pain and fever.
M01AE02 - naproxen ; Belongs to the class of propionic acid derivatives of non-steroidal antiinflammatory and antirheumatic products.

Rx