Skelan Forte Special 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.