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Black Box Warning
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Cardiovascular Risk · Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction and stroke, which can be fatal. This risk may increase with duration of use. Patients with CV disease or risk factors for CV disease may be at greater risk. · Diclofenac sodium tablets are contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. Gastrointestinal Risk · NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events, including inflammation, bleeding, ulceration and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious GI events. |
Qualitative and Quantitative Composition
Each prolonged-release tablet contains:
Diclofenac Sodium IP………………………………….100 mg
Colour: Titanium Dioxide IP
Dosage Form and Strength
Prolonged-release tablet, 100 mg
Clinical Particulars
Therapeutic Indications
REACTIN – 100 SR tablets are indicated for relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis.
Posology and Method of Administration
For the relief of osteoarthritis and rheumatoid arthritis, the recommended dosage is one tablet (100 mg daily).
Or as directed by the Physicians.
Tablets should be swallowed whole, not chewed.
Contraindications
REACTIN – 100 SR tablets are contraindicated in patients with the following conditions:
· Hypersensitivity to diclofenac and/ or any other constituents.
· Patients with active peptic ulcer/haemorrhage or perforation or who have active GI bleeding or other active bleedings, e.g. cerebrovascular bleedings.
· Pregnant women and in women planning a pregnancy.
· Women of childbearing potential who are not using effective contraception
· Patients with a known hypersensitivity to diclofenac, acetylsalicylic acid, other NSAIDs, misoprostol, other prostaglandins, or any other ingredient of the product.
· Patients in whom attacks of asthma, urticaria or acute rhinitis are precipitated by acetylsalicylic acid or other NSAIDs.
· Treatment of peri-operative pain in the setting of CABG surgery.
· Patients with severe renal and hepatic failure.
· Established congestive heart failure (NYHA II–IV), ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
Special Warnings and Precautions for Use
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.
The concomitant use of diclofenac sodium tablets with systemic NSAIDs, including cyclooxygenase-2 (COX2) selective inhibitors, should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects.
Caution is indicated in the elderly on basic medical grounds. In particular, it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight.
As with other NSAIDs, including diclofenac sodium, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction. Presenting symptoms of such reactions can include chest pain occurring in association with an allergic reaction to diclofenac.
Like other NSAIDs, diclofenac sodium may mask the signs and symptoms of infection due to its pharmacodynamic properties.
REACTIN – 100 SR tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.
The pharmacological activity of REACTIN – 100 SR tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed non-infectious, painful conditions.
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimise the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious GI events.
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of MI and stroke. NSAIDs are contraindicated in the setting of CABG.
Post-MI Patients
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of re-infarction, CV-related death and all-cause mortality, beginning in the first week of treatment. In this same cohort, the incidence of death in the first-year post-MI was 20 per 100 person years in NSAID-treated patients compared with 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first-year post-MI, the increased relative risk of death in NSAID users persisted over at least the next 4 years of follow-up.
Avoid the use of REACTIN – 100 SR tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If REACTIN – 100 SR tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischaemia.
Hypertension
NSAIDs, including REACTIN – 100 SR tablets, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin-converting enzyme (ACE) inhibitors, thiazides diuretics or loop diuretics may have impaired response to these therapies when taking NSAIDs.
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Oedema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomised controlled trials demonstrated an approximately 2-fold increase in hospitalisation for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalisation for heart failure, and death.
Additionally, fluid retention and oedema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g. diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).
Avoid the use of REACTIN – 100 SR tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If REACTIN – 100 SR tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
GI Effects: Risk of GI Ulceration, Bleeding and Perforation
NSAIDs, including REACTIN – 100 SR tablets, can cause serious GI adverse events, including inflammation, bleeding, ulceration and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only 1 in 5 patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2–4% of patients treated for 1 year. However, even short-term therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared with patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants or selective serotonin-reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimise the GI Risks in NSAID-Treated Patients
· Use the lowest effective dose for the shortest possible duration.
· Avoid administration of more than one NSAID at a time.
· Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
· Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
· If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue REACTIN – 100 SR tablets until a serious GI adverse event is ruled out.
· In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding.
Renal Toxicity and Hyperkalaemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolaemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state.
No information is available from controlled clinical studies regarding the use of REACTIN – 100 SR tablets in patients with advanced renal disease. The renal effects of REACTIN – 100 SR tablets may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating REACTIN – 100 SR tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolaemia during use of REACTIN – 100 SR tablets. Avoid the use of REACTIN – 100 SR tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If REACTIN – 100 SR tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalaemia
Increases in serum potassium concentration, including hyperkalaemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
Hepatic Effects
Elevations of one or more liver tests may occur during therapy with REACTIN – 100 SR tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e. less than 3 times the ULN [ULN = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.
In clinical trials of diclofenac-containing products, meaningful elevations (i.e. more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).
In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2–6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared with other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.
Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.
In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month and, in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
In a European retrospective population-based, case-controlled study, 10 cases of diclofenac sodium-associated, drug-induced liver injury with current use compared with non-use of diclofenac sodium were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac sodium, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.
Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac sodium, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4–8 weeks after initiating treatment with diclofenac sodium. However, severe hepatic reactions can occur at any time during treatment with diclofenac sodium.
If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, abdominal pain, diarrhoea, dark urine, etc.), REACTIN – 100 SR tablets should be discontinued immediately.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g. nausea, fatigue, lethargy, diarrhoea, pruritus, jaundice, right upper quadrant tenderness, and ‘flu-like’ symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), discontinue REACTIN – 100 SR tablets immediately, and perform a clinical evaluation of the patient.
To minimise the potential risk for an adverse liver related event in patients treated with REACTIN – 100 SR tablets, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing REACTIN – 100 SR tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g. antibiotics, anti-epileptics).
Anaphylactic Reactions
Diclofenac sodium has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac sodium and in patients with aspirin-sensitive asthma.
Skin Reactions
NSAIDs, including diclofenac sodium, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. REACTIN – 100 SR tablets are contraindicated in patients with previous serious skin reactions to NSAIDs.
Haematological Effects
Anaemia is sometimes seen in patients receiving NSAIDs, including REACTIN – 100 SR tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including REACTIN – 100 SR tablets, should have their haemoglobin or haematocrit checked if they exhibit any signs or symptoms of anaemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving REACTIN – 100 SR tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, REACTIN – 100 SR tablets are contraindicated in patients with this form of aspirin sensitivity. When REACTIN – 100 SR tablets are used in patients with pre-existing asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Premature Closure of Foetal Ductus Arteriosus
Diclofenac sodium may cause premature closure of the foetal ductus arteriosus. Avoid use of NSAIDs, including REACTIN – 100 SR tablets, in pregnant women starting at 30 weeks of gestation (third trimester).
Female Fertility
The use of diclofenac sodium may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac sodium should be considered
Drug Interactions
The following interactions include those observed with REACTIN – 100 SR tablets and/or other pharmaceutical forms of diclofenac.
Aspirin: When diclofenac sodium is administered with aspirin, its protein-binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac sodium and aspirin is not generally recommended because of the potential of increased adverse effects.
Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
Cyclosporine: Diclofenac sodium, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with diclofenac sodium may increase cyclosporine’s nephrotoxicity. Caution should be used when REACTIN – 100 SR tablets are administered concomitantly with cyclosporine.
ACE Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors.
Furosemide: Clinical studies, as well as postmarketing observations, have shown that diclofenac sodium can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.
Lithium: NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Steady-state plasma lithium and digoxin levels may be increased and ketoconazole levels may be decreased.
Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
CYP2C9 Inhibitors or Inducers: Diclofenac sodium is metabolised by cytochrome (CY) P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac sodium with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac sodium whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac sodium. Use caution when dosing diclofenac sodium with CYP2C9 inhibitors or inducers; a dosage adjustment may be warranted.
Voriconazole: When co-administered with voriconazole (inhibitor of CYP2C9, 2C19 and 3A4 enzyme), the Cmax and AUC of diclofenac sodium increased by 114% and 78%, respectively.
Other Interactions: There is a possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Cases of hypo- and hyperglycaemia have been reported when diclofenac sodium was associated with antidiabetic agents.
Concomitant use with other NSAIDs or with corticosteroids may increase the frequency of side effects generally.
NSAIDs can reduce the efficacy of diuretics and other antihypertensive drugs, including ACE inhibitors, angiotensin II antagonists (AIIA) and beta-blockers.
In patients with impaired renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the co-administration of an ACE inhibitor or an AIIA and/or diuretics with a COX2 inhibitor can increase the deterioration of the renal function, including the possibility of acute renal failure, which is usually reversible.
Quinolone Antimicrobials: Convulsions may occur due to an interaction between quinolones and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID.
Phenytoin: When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.
Colestipol and Cholestyramine: These agents can induce a delay or decrease in absorption of diclofenac sodium. Therefore, it is recommended to administer diclofenac sodium at least 1 hour before or 4–6 hours after administration of colestipol/cholestyramine.
Cardiac Glycosides: Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
NSAIDs should not be used for 8–12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Use in Special Populations
Pregnant Women
Use of NSAIDs, including REACTIN – 100 SR tablets, during the third trimester of pregnancy increases the risk of premature closure of the foetal ductus arteriosus. Avoid use of NSAIDs, including REACTIN – 100 SR tablets, in pregnant women starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of REACTIN – 100 SR tablets, in pregnant women. Data from observational studies regarding potential embryo-foetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general US population, all clinically recognised pregnancies, regardless of drug exposure, have a background rate of 2–4% for major malformations, and 15–20% for pregnancy loss. In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac sodium daily during the period of organogenesis at doses up to approximately 0.5 times, 0.5 times and 1 time, respectively, the maximum recommended human dose (MRHD) of REACTIN – 100 SR tablets, despite the presence of maternal and foetal toxicity at these doses. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualisation. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac sodium, resulted in increased pre-and post-implantation loss.
Animal Data
Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and foetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0.5 times the maximum recommended human dose [MRHD] of REACTIN – 100 SR tablets, 200 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.5 and 1 times, respectively, the MRHD based on BSA comparison). In a study in which pregnant rats were orally administered 2 mg/kg or 4 mg/kg diclofenac (0.1 and 0.2 times the MRHD based on BSA) from gestation day 15 through lactation day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced foetal weights and growth, and reduced foetal survival. Diclofenac sodium has been shown to cross the placental barrier in mice, rats, and humans.
Labour and Delivery
There are no studies on the effects of REACTIN – 100 SR tablets during labour or delivery. In animal studies, NSAIDs, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Lactating Women
Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for REACTIN – 100 SR tablets and any potential adverse effects on the breastfed infant from the REACTIN – 100 SR tablets or from the underlying maternal condition.
Data
One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac sodium was not detectable in breast milk in 12 women using diclofenac sodium (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period).
Paediatric Patients
Safety and effectiveness in paediatric patients have not been established.
Geriatric Patients
Elderly patients, compared with younger patients, are at greater risk for NSAID-associated serious CV, GI, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects.
Diclofenac sodium is known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Female Fertility
As with other NSAIDs, the use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac sodium should be considered
Effects on Ability to Drive and Use Machines
Patients who experience dizziness or other central nervous system disturbances while taking NSAIDs should refrain from driving or operating machinery.
Undesirable Effects
In patients taking diclofenac sodium tablets, or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1–10% of patients are as follows:
GI Events: These include abdominal pain, constipation, diarrhoea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting.
Other: Abnormal renal function, anaemia, dizziness, oedema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus.
Additional adverse experiences reported occasionally include the following:
Body as a Whole: fever, infection, sepsis
CV System: congestive heart failure, hypertension, tachycardia, syncope
Digestive System: dry mouth, oesophagitis, gastric/peptic ulcers, gastritis, GI bleeding, glossitis, haematemesis, hepatitis, jaundice.
Haemic and Lymphatic System: ecchymosis, eosinophilia, leucopaenia, melaena, purpura, rectal bleeding, stomatitis, thrombocytopaenia
Metabolic and Nutritional: weight changes
Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities,
drowsiness, insomnia, malaise, nervousness, paraesthesia, somnolence, tremors, vertigo
Respiratory System: asthma, dyspnoea
Skin and Appendages: rash, alopecia, photosensitivity, sweating increased
Special Senses: blurred vision
Urogenital System: cystitis, dysuria, haematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure
Immune System Disorders: Hypersensitivity
Other adverse reactions, which occur rarely, are as follows
Body as a Whole: anaphylactic reactions, appetite changes, death
CV System: arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis
Digestive System: colitis, eructation, fulminant hepatitis with and without jaundice, liver failure, liver necrosis, pancreatitis.
Haemic and Lymphatic System: agranulocytosis, haemolytic anaemia, aplastic anaemia, lymphadenopathy, pancytopaenia
Metabolic and Nutritional: hyperglycaemia
Nervous System: convulsions, coma, hallucinations, meningitis, paraesthesia, memory impairment, anxiety, tremor, taste disturbances, cerebrovascular accident.
Respiratory System: respiratory depression, pneumonia
Skin and Appendages: angio-oedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria
Special Senses: conjunctivitis, hearing impairment
Immune System Disorders: angioneurotic oedema (including face oedema)
Eye Disorders: visual disturbance, vision blurred, diplopia
Ear and Labyrinth Disorders: tinnitus, hearing impaired
Reproductive System: impotence
Nicolau’s syndrome, also known as livedo-like dermatitis or embolia cutis medicamentosa, is a rare complication reported following intramuscular diclofenac sodium injection.
If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.
Overdose
Symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, confusion, disorientation, excitation, coma, tinnitus, fainting or convulsions, vomiting, headache, dizziness and epigastric pain, which are generally reversible with supportive care. GI complaints, including GI bleeding, can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. In the case of significant poisoning, acute renal failure and liver damage are possible.
Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60–100 g in adults, 1–2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5–10 times the usual dose). Forced diuresis, alkalinisation of urine, haemodialysis or haemoperfusion may not be useful due to high protein-binding.
Management of acute poisoning with NSAIDs essentially consists of supportive and symptomatic measures. It is reasonable to take measures to reduce absorption of any recently consumed drug by forced emesis, gastric lavage or activated charcoal. Induced diuresis may be beneficial because diclofenac and misoprostol metabolites are excreted in the urine, provided that the patient does not develop renal failure at diclofenac overdose. Special measures such as haemodialysis or haemoperfusion are probably unlikely to be helpful in accelerating the elimination of diclofenac, due to the high protein binding and extensive metabolism.
Pharmacological Properties
Mechanism of Action
REACTIN – 100 SR tablets have analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of REACTIN – 100 SR tablets, like that of other NSAIDs, is not completely understood but involves inhibition of COX-1 and COX-2. Diclofenac sodium is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac sodium concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac sodium is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.
Pharmacodynamic Properties
Pharmacotherapeutic group: Non-steroidal anti-inflammatory drugs (NSAlDs) that has been shown to have anti-inflammatory and analgesic properties and is effective in treating the signs and symptoms of arthritic conditions.
Pharmacokinetic Properties
Absorption
Diclofenac sodium is 100% absorbed after oral administration compared to intravenous (IV) administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. When REACTIN – 100 SR tablets are taken with food, there is a delay of 1–2 hours in the Tmax and a 2-fold increase in Cmax values. The extent of absorption of diclofenac sodium, however, is not significantly affected by food intake.
Distribution
The apparent volume of distribution (V/F) of diclofenac sodium is 1.4 L/kg. Diclofenac sodium is more than 99% bound to human serum proteins, primarily to albumin. Serum protein-binding is constant over the concentration range (0.15–105 μg/mL) achieved with recommended doses.
Diclofenac sodium diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac sodium.
Metabolism
Five diclofenac sodium metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3' hydroxy-4'-methoxy-diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4’-hydroxy- diclofenac is primarily mediated by
Excretion
Diclofenac sodium is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulphate conjugates of the metabolites. Little or no free unchanged diclofenac sodium is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac sodium plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac sodium, dosing adjustment in patients with mild-to-moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac sodium is approximately 2 hours.
Non-Clinical Properties
Animal Toxicology or Pharmacology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.1 times the maximum recommended human dose (MRHD) of REACTIN – 100 SR tablets, 200 mg/day (based on BSA comparison), have revealed no significant increase in tumour incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.007 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.02 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential.
Mutagenesis
Diclofenac sodium did not show mutagenic activity in in vitro point-mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters.
Impairment of Fertility
Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0.2 times the MRHD based on BSA comparison) did not affect fertility.
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including REACTIN – 100 SR tablets, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including REACTIN – 100 SR tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Description
REACTIN – 100 SR tablets contain diclofenac sodium, which is a NSAID that exhibits anti-inflammatory, analgesic and antipyretic activities in animal models. The mechanism of action of diclofenac sodium, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
Pharmaceutical Particulars
Incompatibilities
Not applicable.
Shelf-Life
As on the pack.
Packaging Information
Aluminium strip pack of 10 tablets
Aluminium strip pack of 15 tablets
Storage and Handling Instructions
Store in a cool dry place.
Protect from light
Keep out of reach of children
Patient Counselling Information
· What is REACTIN – 100 SR tablets?
REACTIN – 100 SR tablets contain diclofenac sodium, which belongs to a group of medicinal products called NSAIDs and is indicated for relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis.
· Do not take if you have an allergy to this drug
Do not take REACTIN – 100 SR tablets if you are hypersensitive to diclofenac sodium, aspirin, ibuprofen or/and other NSAIDs or/and any of the other ingredients of this medicine.
· Before you take REACTIN – 100 SR tablets, tell your HCP about other medication.
Some medicines can affect the way other medicines work. Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including the following:
· Aspirin (acetylsalicylic acid) or other NSAIDs (e.g. ibuprofen)
· Medicines used to treat osteoarthritis or rheumatoid arthritis known as cyclo-oxygenase-2 (COX2) inhibitors
· Diuretics (used to treat excess fluid in the body)
· Cyclosporine or tacrolimus (used for immune system suppression, e.g. after transplants)
· Lithium (used to treat some types of depression)
· Digoxin (a medicine for an irregular heart beat and/or heart failure)
· Warfarin or other oral anticoagulants (blood-thinning agents that reduce blood clotting, e.g. aspirin)
· Medicines used to treat anxiety and depression known as selective serotonin-re-uptake inhibitors (SSRIs)
· Medicines used to control your blood sugar (oral hypoglycaemics for diabetes)
· Methotrexate (used to treat rheumatoid arthritis, psoriasis and leukaemia)
· Steroid medications (e.g. corticosteroids, which are often used as anti-inflammatory medicines)
· Medicines for high blood pressure (anti-hypertensives)
· Magnesium containing antacids (used to treat heartburn, indigestion)
· Quinolone antibiotics (used to treat some infections)
· Ketoconazole, fluconazole, miconazole and voriconazole (used to treat some fungal infections)
· Amiodarone (used to treat an abnormal heart beat)
· Sulphinpyrazole (used to treat gout)
· If you have taken a medicine called mifepristone (used to terminate pregnancy) within the last 12 days, diclofenac should not be taken within 8–12 days of taking mifepristone
· Medicines for nausea or sickness, such as metoclopramide or domperidone
· Colestyramine for high cholesterol or high blood fats
· Imatinib, used to treat certain cancers
· Some antibiotics (chloramphenicol)
· Any other tablets or medicines, including any not prescribed by your doctor.
· How should I take REACTIN – 100 SR tablets?
Always use REACTIN – 100 SR tablets exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.
· What are the possible side effects?
Like all medicines, this medicine can cause side effects although not everybody gets them. Some side effects can be serious; STOP TAKING REACTIN – 100 SR tablets and tell your doctor straightaway if you notice the following:
· Stomach pain, indigestion, heartburn, wind, nausea (feeling sick) or vomiting (being sick)
· Any sign of bleeding in the stomach or intestine, e.g. when emptying your bowels, blood in vomit or black, tarry faeces
· Allergic reactions, which can include skin rash, itching, bruising, painful red areas, peeling or blistering
· Wheezing or shortness of breath (bronchospasm)
· Swollen, face, lips, hands or fingers
· Yellowing of your skin or the whites of your eyes
· Persistent sore throat or high temperature
· An unexpected change in the amount of urine produced and/or its appearance.
· Mild cramping and tenderness of the abdomen, starting shortly after the start of the treatment with REACTIN – 100 SR tablets and followed by rectal bleeding or bloody diarrhoea usually within 24 hours of the onset of abdominal pain
· Stevens-Johnson syndrome (serious illnesses with blistering of the skin, mouth, eyes and genitals)
Tell your doctor immediately if you notice the following:
· Chest pain, which can be a sign of a potentially serious allergic reaction called Kounis syndrome
If you notice that you are bruising more easily than usual or have frequent sore throats or infections, tell your doctor.
The side effects listed below have also been reported.
Common (may affect up to 1 in 10 people)
· Stomach pain, heartburn, nausea, vomiting, diarrhoea, indigestion, wind, loss of appetite
· Headache, dizziness, vertigo
· Skin rash or spots
· Raised levels of liver enzymes in the blood
Rare (may affect up to 1 in 1,000 people)
· Stomach ulcers or bleeding (there have been very rare reported cases resulting in death, particularly in the elderly)
· Gastritis (inflammation, irritation or swelling of the stomach lining)
· Vomiting blood
· Diarrhoea with blood in it or bleeding from the back passage
· Black, tarry faeces or stools
· Drowsiness, tiredness
· Hypotension (low blood pressure, symptoms of which may include faintness, giddiness or light headedness)
· Skin rash and itching
· Fluid retention, symptoms of which include swollen ankles
· Liver function disorders, including hepatitis and jaundice
Very rare (may affect up to 1 in 10,000 people) Effects on the nervous system
Tingling or numbness in the fingers, tremor, blurred or double vision, hearing loss or impairment, tinnitus (ringing in the ears), sleeplessness, nightmares, mood changes, depression, anxiety, mental disorders, disorientation and loss of memory, fits, headaches together with a dislike of bright lights, fever and a stiff neck, disturbances in sensation.
Effects on the stomach and digestive system
Constipation, inflammation of the tongue, mouth ulcers, inflammation of the inside of the mouth or lips, taste changes, lower gut disorders (including of the colon or worsening of ulcerative colitis or Crohn’s disease).
Effects on the heart, chest or blood
Palpitations (fast or irregular heart beat), chest pain, hypertension (high blood pressure), inflammation of blood vessels (vasculitis), inflammation of the lung (pneumonitis), heart disorders, including congestive heart failure or heart attack, blood disorders (including anaemia).
Effects on the liver or kidneys
Kidney or severe liver disorders including liver failure, presence of blood or protein in the urine.
Effects on skin or hair
Serious skin rashes, including Stevens-Johnson syndrome, Lyell’s syndrome and other skin rashes which may be made worse by exposure to sunlight; hair loss.
Other side effects that have also been reported include the following:
· Inflammation of the pancreas, impotence
· Facial swelling, inflammation of the lining of the brain (meningitis), stroke, throat disorders, confusion, hallucinations, malaise (general feeling of discomfort), inflammation of the nerves in the eye
Do not be alarmed by this list – most people take REACTIN – 100 SR tablets without any problems. If any of the side effects becomes serious, or if you notice side effects not listed in this leaflet, please tell your doctor. He/she may want to give you a different medicine.
· How should I store REACTIN – 100 SR tablets?
Keep this medicine out of the sight and reach of children.
Store in a dry place and protect from light.
Store in the original packaging.
Do not use this medicine after the expiry date stated on the blister pack and carton. The expiry date refers to the last day of that month.
· General information about the safe and effective use of this drug.
REACTIN – 100 SR tablets contain diclofenac sodium, which is indicated for relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis.
Do not take this medicine if
· you are allergic to diclofenac sodium, aspirin, ibuprofen or to any other NSAID, or any of the other ingredients of REACTIN – 100 SR tablets. Signs of a hypersensitivity reaction include swelling of the face and mouth (angioedema), breathing problems, chest pain, runny nose, skin rash or any other allergic type reaction;
· you have now, or have ever had, a stomach (gastric) or duodenal (peptic) ulcer, or bleeding in the digestive tract (this can include blood in vomit, bleeding when emptying bowels, fresh blood in faeces or black, tarry faeces);
· you have had stomach or bowel problems after you have taken other NSAIDs;
· you have severe heart, kidney or liver failure you have established heart disease and/or cerebrovascular disease, e.g. if you have had a heart attack, stroke, mini-stroke (TIA) or blockages to blood vessels to the heart or brain or an operation to clear or bypass blockages;
· you have or have had problems with your blood circulation (peripheral arterial disease); and/or
· you are more than 6 months pregnant.
Talk to your doctor or pharmacist before taking diclofenac if
· you suffer from any stomach or bowel disorders, including ulcerative colitis or Crohn’s disease;
· you have kidney or liver problems, or you are elderly;
· you have a condition called porphyria;
· you suffer from any blood or bleeding disorder. If you do, your doctor may ask you to go for regular check-ups while you are taking these tablets;
· you ever had asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (nasal polyps), chronic pulmonary diseases or infections of the respiratory tract;
· you are breastfeeding;
· you have angina, blood clots, high blood pressure, raised cholesterol or raised triglycerides;
· you have heart problems or if you had a stroke or you think you might be at risk of these conditions (e.g. if you have high blood pressure, diabetes or high cholesterol or are a smoker);
· you have diabetes;
· you smoke; and/or
· you have systemic lupus erythematosus ([SLE] an inflammatory, auto-immune disorder that causes symptoms such as joint pain, joint inflammation, skin rashes, fever) or any similar condition.
If you feel dizzy or drowsy after taking REACTIN – 100 SR tablets, do not drive and do not use any tools or machines until these effects have worn off.
Tell your doctor if you recently had or you are going to have a surgery of the stomach or intestinal tract before taking REACTIN – 100 SR tablets, as it can sometimes worsen wound healing in your gut after surgery.
· What are the ingredients?
REACTIN – 100 SR tablets contain diclofenac sodium 100 mg.
· Any other information
Before you are given this medicine, make sure your doctor knows if you
• smoke;
• have diabetes; and/or,
• have angina, blood clots, high blood pressure, raised cholesterol or raised triglycerides
This medicine may be associated with a small increased risk of heart attack (myocardial infarction) or stroke. Any risk is more likely with high doses and prolonged treatment. Do not exceed the recommended dose or duration of treatment.
Side effects may be minimised by using the lowest effective dose for the shortest duration necessary.
As with other NSAIDs (e.g. ibuprofen), REACTIN – 100 SR tablets may lead to an increase in blood pressure and, so, your doctor may advise you to monitor your blood pressure on a regular basis.
If you have heart, liver or kidney problems, your doctor will advise regular monitoring of the same.
Details of the Manufacturer
Mfd. By Cipla Ltd.
Registered Office:
Cipla House, Peninsula Business Park,
Ganpatrao Kadam Marg
Lower Parel
Mumbai – 400 013, India
Details of Permission or Licence Number with Date
M.L. No. 27/UA/LL/2006
Date of Revision
20/01/2020
