Black Box WarningCardiovascular 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 potassium 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 film coated tablet contains:
Diclofenac Potassium BP…………………………………..50 mg
Paracetamol IP……………………………………………..325 mg
Serratiopeptidase IP………………………………………..10 mg
Dosage Form and Strength
Diclofenac Potassium 50mg, Paracetamol 325mg and Serratiopeptidase 10mg oral tablets
Clinical Particulars
Therapeutic Indications
CIPZEN D PLUS Tablet is a combination medicine used for following conditions:
· Quick relief from pain for the longer duration
· Also for Inflammatory swelling & oedema
Posology and Method of Administration
As directed by the physician
Tablets should be swallowed whole, not chewed.
Contraindications
CIPZEN D PLUS Tablets are contraindicated in patients with the following conditions:
· Hypersensitivity to diclofenac and/ or paracetamol and/or Serratiopeptidase and/or 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
Diclofenac Potassium
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. The use of Diclofenac potassium with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects
Elderly
Caution is indicated in the elderly on basic medical grounds. The elderly have increased frequency of adverse reactions to NSAIDs especially gastro intestinal bleeding and perforation which may be fatal. In particular, it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight.
Gastrointestinal
Close medical surveillance is imperative in patients with symptoms indicative of gastrointestinal disorders, with a history suggestive of gastric or intestinal ulceration, bleeding or perforation, with ulcerative colitis, or with Crohn's disease as these conditions may be exacerbated.
Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.
GI bleeding (haematemesis, melaena), ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. They generally have more serious consequences in the elderly.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence and maintain treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk.
Caution should be advised in patients receiving concomitant medications which increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet agents such as aspirin.
When GI bleeding or ulceration occurs in patients receiving diclofenac potassium, the treatment should be withdrawn.
Hypersensitivity reactions
As with other non-steroidal anti-inflammatory drugs, allergic reactions, including anaphylactic/anaphylactoid reactions, can occur without earlier exposure to the drug.
Infection
Like other NSAIDs, Diclofenac Potassium tablets may mask the signs and symptoms of infection due to their pharmacodynamic properties.
SLE and mixed connective tissue disease
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.
Cardiovascular, Renal and Hepatic Impairment
The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure.
As fluid retention and oedema have been reported in association with NSAIDs therapy, including diclofenac, particular caution is called for in patients with impaired cardiac or renal function, history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery. Monitoring of renal function is recommended as a precautionary measure when using diclofenac in such cases. Discontinuation therapy is usually followed by recovery to the pre-treatment state.
Hepatic
Close medical surveillance is required when prescribing diclofenac to patients with impairment of hepatic function as their condition may be exacerbated.
As with other NSAIDs, including diclofenac, values of one or more liver enzymes may increase. During prolonged treatment with Diclofenac, regular monitoring of hepatic function is indicated as a precautionary measure. If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Diclofenac Potassium tablets should be discontinued.
Hepatitis may occur without prodromal symptoms.
Use of Diclofenac Potassium tablets in patients with hepatic porphyria may trigger an attack.
Haematological
Diclofenac Potassium tablets may reversibly inhibit platelet aggregation. Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.
Long term treatment
All patients who are receiving long term treatment with non-steroidal, anti-inflammatory agents should be monitored as a precautionary measure e.g. renal function, hepatic function (elevation of liver enzymes may occur) and blood counts. This is particularly important in the elderly.
Respiratory disorders
In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions on NSAIDs like asthma exacerbations (so called intolerance to analgesics / analgesics asthma), Quincke's oedema or urticaria are more frequent than in other patients. Therefore, special precaution is recommended in such patients (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.
Like other drugs that inhibit prostaglandin synthetase activity, diclofenac potassium and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of bronchial asthma.
Cardiovascular and cerebrovascular effects
Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy including diclofenac.
Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease and with significant risk factors for cardiovascular events (e.g. hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration.
As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically.
Dermatological
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Diclofenac potassium should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Impaired female fertility
The use of Diclofenac Potassium tablets 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 Potassium tablets should be considered.
Paracetamol
Use in Special Populations
Paediatric Patients
Not recommended for children under 10 years of age.
Patients with Renal/Hepatic Impairment
Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with alcoholic liver disease.
Keep out of the sight and reach of children.
Do not take paracetamol for more than 3 days without consulting a doctor.
Patients should be advised that paracetamol may cause severe skin reactions. If a skin reaction such as reddening, blisters or rash occurs, they should stop its use and seek medical assistance right away.
Drug Interactions
Diclofenac Potassium
Other NSAIDs including cyclooxygenase-2 selective inhibitors and corticosteroids: Co-administration of diclofenac with other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs.
Diuretics and antihypertensive agents: Like other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.
Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity.
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Lithium: If used concomitantly, diclofenac may increase plasma concentrations of lithium Monitoring of the serum lithium level is recommended.
Methotrexate: Diclofenac can inhibit the tubular renal clearance of methotrexate hereby increasing methotrexate levels. Caution is recommended when NSAIDs, including diclofenac, are administered less than 24 hours before treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increase. Cases of serious toxicity have been reported when methotrexate and NSAIDs including diclofenac are given within 24 hours of each other. This interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSAID.
Ciclosporin: Diclofenac, like other NSAIDs, may increase the nephrotoxicity of ciclosporin due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Anti-coagulants and anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding. Although clinical investigations do not appear to indicate that diclofenac has an influence on the effect of anticoagulants, there are reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulant concomitantly. Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other nonsteroidal anti-inflammatory agents, diclofenac in a high dose can reversibly inhibit platelet aggregation. NSAID
Digoxin: If used concomitantly, diclofenac may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.
Selective serotonin reuptake inhibitors (SSRls): lncreased risk of gastrointestinal bleeding.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. This might be mediated through renal antiprostagladin effects of both NSAID and calcineurin inhibitor.
Quinolone antibacterials: 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.
Therefore, it is recommended to administer diclofenac at least one hour before or 4 to 6 hours after administration of colestipol/ cholestyramine.
Zidovudine: lncreased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
Antidiabetic agents: Clinical studies have shown that Diclofenac Potassium tablets can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects which have required adjustment to the dosage of hypoglycaemic agents. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.
Drugs known to cause hyperkalemia: Concomitant treatment with potassium-sparing diuretics, ciclosporin, tacrolimus or trimethoprim may be associated with increased serum potassium levels, which should therefore be monitored frequently.
Potent CYP2C9 inhibitors: Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.
Paracetamol
The speed of absorption of paracetamol may be increased by metoclopramide or domperidone. However, concurrent use need not be avoided.
The speed of absorption of paracetamol is reduced by colestyramine. Therefore, colestyramine should not be taken within 1 hour if maximal analgesia is required.
The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.
Restriction or avoidance of concomitant regular paracetamol use should be followed with imatinib.
Chloramphenicol plasma concentration is increased when given with paracetamol.
Serratiopeptidase
Patients on anticoagulant therapy should be observed carefully because of possible potentiation of anticoagulant effects by Serratiopeptidase.
Use in Special Populations
Pregnant Women
Diclofenac Potassium
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and or cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1% up to approximately 1.5%.
The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has shown to result in increased pre-and post-implantation loss and embryo-foetal lethality.
In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during organogenetic period. NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus. If diclofenac is used by a woman attempting to conceive, or during the 1st or 2nd trimesters of pregnancy, the dose should be kept as low and duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:
· cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)
· renal dysfunction, which may progress to renal failure with oligo-hydroamniosis
The mother and the neonate, at the end of the pregnancy, to:
· possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses
· inhibition of uterine contractions resulting in delayed or prolonged labour
Consequently, diclofenac is contra-indicated during the third trimester of pregnancy.
Paracetamol
Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.
A large amount of data on pregnant women indicate neither malformative, nor foeto-/neonatal toxicity. Paracetamol can be used during pregnancy if clinically needed; however, it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.
In late pregnancy, as with other NSAIDs, CIPZEN D PLUS Tablets should be avoided because they may cause premature closure of the ductus arteriosus.
Serratiopeptidase
Not enough is known about the use of Serratiopeptidase during pregnancy.
Labour and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of diclofenac on labour and delivery in pregnant women are unknown.
Lactating Women
Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore, Diclofenac should not be administered during breast feeding in order to avoid undesirable effects in the infant.
Not enough information is known about the use of Serratiopeptidase during lactation.
Paracetamol is excreted in breast milk but not in clinically significant amount. Available published data do not contraindicate breastfeeding.
Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CIPZEN D PLUS Tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Paediatric Patients
Safety and effectiveness in paediatric patients have not been established.
Geriatric Patients
As with any NSAIDs, caution should be exercised in treating the elderly (65 years of age and older).
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
Diclofenac Potassium
Adverse reactions are ranked under the heading of frequency, the most frequent first, using the following convention:
very common: (>1/10); common (≥ 1/100, <1/10); uncommon (≥ 1/1,000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); Unknown: cannot be estimated from available data.
The following undesirable effects include those reported with other short-term or long-term use.
Blood and lymphatic system disorders.
Very rare: Thrombocytopenia, leucopoenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.
Unknown: Neutropenia
Immune system disorders
Rare: Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).
Very rare: Angioneurotic oedema (including face oedema).
Psychiatric disorders
Very rare: Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.
Nervous system disorders
Common: Headache, dizziness.
Rare: Somnolence, tiredness.
Very rare: Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis*, taste disturbances, cerebrovascular accident.
Unknown: Confusion, hallucinations, disturbances of sensation malaise
* especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease, with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation.
Eye disorders
Very rare: Visual disturbance, vision blurred, diplopia.
Unknown: Optic neuritis.
Ear and labyrinth disorders
Common: Vertigo.
Very rare: Tinnitus, hearing impaired.
Cardiac disorders
Very rare: Palpitations, chest pain, cardiac failure, myocardial infarction.
Vascular disorders
Very rare: Hypertension, hypotension, vasculitis.
Respiratory, thoracic and mediastinal disorders
Rare: Asthma (including dyspnoea).
Very rare: Pneumonitis.
Gastrointestinal disorders
Common: Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia.
Rare: Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer with or without bleeding or perforation (sometimes fatal particularly in the elderly).
Very rare: Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis.
Unknown: Ischaemic colitis.
Hepatobiliary disorders
Common: Transaminases increased.
Rare: Hepatitis, jaundice, liver disorder.
Very rare: Fulminant hepatitis, hepatic necrosis, hepatic failure.
Skin and subcutaneous tissue disorders
Common: Rash.
Rare: Urticaria.
Very rare: Bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), dermatitis exfoliative, loss of hair, photosensitivity reaction, purpura, allergic purpura, pruritus.
Renal and urinary disorders
Very rare: Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.
General disorders and administration site conditions
Rare: Oedema
Reproductive system and breast disorders
Very rare: Impotence
Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150mg daily) and in long term treatment.
Paracetamol
The information below lists reported adverse reactions, ranked using the following frequency classification: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Immune System Disorders
Hypersensitivity, including skin rash, may occur
NOT KNOWN: anaphylactic shock, angio-oedema
Blood and Lymphatic System Disorders
NOT KNOWN: blood dyscrasias, including thrombocytopaenia and agranulocytosis
Skin and Subcutaneous Disorders
Very rare cases of serious skin reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, and fixed drug eruption have been reported.
Serratiopeptidase
Serratiopeptidase was well tolerated in short-term clinical trials, but long-term safety has not been evaluated. Rare, serious adverse effects reported with Serratiopeptidase include eosinophilic pneumonitis, bullous pemphigoid, haemorrhage in a patient with Behcet disease and, possibly, Stevens-Johnson syndrome. Its use may cause occasional hypersensitivity, diarrhoea, nausea, vomiting, epistaxis and haemoptysis.
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 (PvPI) by calling on 1800 267 7779 (Cipla number) or you can report to PvPI on 1800 180 3024. By reporting side effects, you can help provide more information on the safety of this product.
Overdose
Diclofenac Potassium
a) Symptoms
There is no typical clinical picture resulting from diclofenac over dosage. Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, dizziness, disorientation, excitation, coma, drowsiness, tinnitus, fainting, occasionally convulsions. In rare cases of significant poisoning acute renal failure and liver damage are possible.
b) Therapeutic measure
Patients should be treated symptomatically as required.
Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.
Good urine output should be ensured. Special measures such as forced diuresis, dialysis or haemo-perfusion are probably of no help in eliminating NSAIDs, including diclofenac, due to high protein binding and extensive metabolism.
Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of potentially toxic amounts.
Frequent or prolonged convulsions should be treated with intravenous diazepam. Supportive measures should be given for complications such as hypotension, renal failure, gastrointestinal disorder, and respiratory depression.
Other measures may be indicated by the patient's clinical condition.
Paracetamol
Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5 g or more of paracetamol may lead to liver damage if the patient has risk factors.
Pharmacological Properties
Mechanism of Action
CIPZEN D PLUS Tablets contain diclofenac potassium, paracetamol and Serratiopeptidase. Diclofenac potassium is a NSAID (non-steroidal anti-inflammatory drug) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of diclofenac potassium, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Paracetamol has analgesic and antipyretic actions. Serratiopeptidase is also a potent anti-inflammatory agent that exerts fibrinolytic and anti-oedematic actions. The therapeutic enzyme reduces inflammation and swelling in the affected area.
Pharmacodynamic Properties
Diclofenac Potassium
Pharmacotherapeutic group (ATC code): M01A B05
Diclofenac Potassium contain the potassium salt of diclofenac, a non-steroidal compound with pronounced and clinically demonstrable analgesic, anti-inflammatory and anti-pyretic properties.
Paracetamol
ATC code: N02B E01, Other analgesics and antipyretics
Analgesic: The mechanism of analgesic action has not been fully determined. Paracetamol may act predominately by inhibiting prostaglandin synthesis in the central nervous system and, to a lesser extent, through a peripheral action by blocking pain-impulse generation.
The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.
Antipyretic: Paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat-regulation centre to produce peripheral vasodilation, resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus. The drug has no effect on the CV and respiratory systems and unlike salicylates, it does not cause gastric irritation or bleeding.
Paracetamol has analgesic and antipyretic actions but it has no useful anti- inflammatory properties.
Serratiopeptidase is a bacterial, peptide-cleaving enzyme obtained from Serratia marcescens
Pharmacokinetic Properties
Diclofenac Potassium
Absorption
Diclofenac is rapidly and completely absorbed from sugar-coated tablets. Food intake does not affect absorption. Peak plasma concentration after one 50 mg sugar-coated tablet was 3.9 μmol/l after 20-60 minutes. The plasma concentrations show a linear relationship to the size of the dose. Diclofenac undergoes first-pass metabolism and is extensively metabolised.
Distribution
Diclofenac is highly bound to plasma proteins (99.7%), chiefly albumin (99.4%). Diclofenac was detected in a low concentration (100ng/mL) in breast milk in one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day dose.
Elimination
The total systemic clearance of diclofenac in plasma is 263 ± 56 ml/min (mean ± SD).
The terminal half-life in plasma is 1 – 2 hours.
Repeated oral administration of Diclofenac Potassium tablets for 8 days in daily doses of 50 mg t.d.s does not lead to accumulation of diclofenac in the plasma.
Approx. 60% of the dose administered is excreted in the urine in the form of metabolites, and less than 1% as unchanged substance. The remainder of the dose is eliminated as metabolites through the bile in the faeces.
Biotransformation
The biotransformation of diclofenac involves partly glucuronidation of the intact molecule but mainly single and multiple hydroxylation followed by glucuronidation.
Characteristics in patients
The age of the patient has no influence on the absorption, metabolism, or excretion of diclofenac.
In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of <10 ml/min the theoretical steady-state plasma levels of metabolites are about four times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.
In the presence of impaired hepatic function (chronic hepatitis, non-decompensated cirrhosis) the kinetics and metabolism are the same as for patients without liver disease.
Paracetamol
Paracetamol is readily absorbed from the GI tract, with peak plasma levels occurring about 30 minutes to 2 hours after ingestion.
It is metabolised in the liver (90–95%) and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted unchanged.
The elimination half-life of paracetamol varies from about 1 to 4 hours. Plasma protein-binding is negligible at usual therapeutic doses but increases with increasing concentrations.
A minor hydroxylated metabolite (N-acetyl-p-benzoquinoneimine), which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione, may accumulate following paracetamol overdosage and cause liver damage.
The time to peak plasma concentration of paracetamol is 0.5–2 hours, the time to peak effect 1–3 hours, and the duration of action is 3–4 hours.
Serratiopeptidase
Serratiopeptidase has been shown to be absorbed from the digestive tract. On oral administration, it is absorbed unchanged into the systemic circulation, from where it penetrates all the tissues. It reaches higher concentrations in the inflamed tissues. It attains peak levels in one hour.
Non-Clinical Properties
Animal Toxicology or Pharmacology
Data not available.
Description
CIPZEN D PLUS Tablets contain diclofenac potassium, paracetamol and Serratiopeptidase. Diclofenac potassium is a NSAID that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of diclofenac potassium, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Paracetamol has analgesic and antipyretic actions.
Serratiopeptidase is an extracellular proteolytic enzyme produced by Serratia marcescens ATCC 27117 (formerly Serratia strain E-15. composed of 470 amino acids, with a molecular weight of approximately 50,000 kilodaltons. The active site of the enzyme, which contains a zinc atom, hydrolyses nonterminal peptide linkages of polypeptides. Maximal proteolytic activity occurs at 40°C (104°F) and at a pH of approximately 8 (range, 6 to 10). Maintaining the temperature at 55°C (131°F) for 15 minutes inactivates the enzyme.
Pharmaceutical Particulars
Incompatibilities
Not applicable.
Shelf-Life
As on the pack.
Packaging Information
Unknown
Storage and Handling Instructions
Unknown
Patient Counselling Information
· What is CIPZEN D PLUS Tablets?
CIPZEN D PLUS Tablets contain diclofenac potassium which belongs to a group of medicinal products called NSAIDs (non-steroidal anti-inflammatory drugs), paracetamol, which has analgesic and antipyretic actions and Serratiopeptidase is an enzyme that works by breaking down abnormal proteins at the site of inflammation and promotes healing.
CIPZEN D PLUS Tablets are used for relieve symptoms such as fever, pain and inflammation associated with musculoskeletal and joint disorders.
· Do not take if you have an allergy to this drug
Do not take CIPZEN D PLUS Tablets if you are hypersensitive to diclofenac potassium or/and other NSAIDs or/and to paracetamol or/and Serratiopeptidase and/or any of the other ingredients of this medicine.
· Before you take CIPZEN D PLUS 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:
o Aspirin (acetylsalicylic acid) or other NSAIDs (e.g. ibuprofen)
o Medicines used to treat osteoarthritis or rheumatoid arthritis known as cyclo-oxygenase-2 (COX2) inhibitors
o Diuretics (used to treat excess fluid in the body)
o Cyclosporine or tacrolimus (used for immune system suppression, e.g. after transplants)
o Lithium (used to treat some types of depression)
o Digoxin (a medicine for an irregular heart beat and/or heart failure)
o Warfarin or other oral anticoagulants (blood-thinning agents that reduce blood clotting, e.g. aspirin)
o Medicines used to treat anxiety and depression known as selective serotonin-re-uptake inhibitors (SSRIs)
o Medicines used to control your blood sugar (oral hypoglycaemics for diabetes)
o Methotrexate (used to treat rheumatoid arthritis, psoriasis and leukaemia)
o Steroid medications (e.g. corticosteroids, which are often used as anti-inflammatory medicines)
o Medicines for high blood pressure (anti-hypertensives)
o Magnesium containing antacids (used to treat heartburn, indigestion)
o Quinolone antibiotics (used to treat some infections)
o Ketoconazole, fluconazole, miconazole and voriconazole (used to treat some fungal infections)
o Amiodarone (used to treat an abnormal heartbeat)
o Sulphinpyrazole (used to treat gout)
o 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
o Medicines for nausea or sickness, such as metoclopramide or domperidone
o Colestyramine for high cholesterol or high blood fats
o Imatinib, used to treat certain cancers
o Some antibiotics (chloramphenicol)
o Any other tablets or medicines, including any not prescribed by your doctor.
· How should I take CIPZEN D PLUS Tablets?
Always use CIPZEN D PLUS Tablets exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.
DO NOT crush or chew the tablets.
· What are the possible side effects?
Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may happen with CIPZEN D PLUS Tablets. If any of the following happen, stop taking this medicine and tell your doctor immediately:
o Swelling of the hands, feet, ankles, face, lips or throat, which may cause difficulty in swallowing or breathing.
o Weakness of or inability to move one side of body, slurred speech (stroke) or chest pain (heart attack) or heart failure or palpitations (awareness of your heartbeat) – the occurrence is uncommon.
o Shortness of breath – the occurrence is uncommon.
o A decrease in a type of white blood cells (these helps protect the body from infection and disease) and can lead to infections with symptoms such as chills, sudden fever, sore throat or flu-like symptoms – the occurrence is uncommon.
o Severe stomach pain or any sign of bleeding or rupture in the stomach or intestines, such as passing black or bloodstained stools – the occurrence is uncommon, or vomiting blood – this occurs rarely.
o A serious skin reaction such as rash, blistering or peeling of the skin (Stevens-Johnson syndrome, exfoliative dermatitis and toxic epidermal necrolysis) – this occurs very rarely.
o A serious allergic reaction such as skin rash, swelling of the face, wheezing or difficulty breathing (anaphylactic shock) – this occurs rarely.
o Jaundice (your skin or the whites of your eyes look yellow) – this occurs rarely.
o Reduction in the number of blood platelets (increased chance of bleeding or bruising) – it is not known how often this occurs.
o Symptoms of meningitis – it is not known how often this occurs.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Very common: may affect more than 1 in 10 people
- Stomach ache, diarrhoea, nausea (feeling sick), indigestion
Diarrhoea is the most common problem and is occasionally severe. You have less chance of getting diarrhoea if you take diclofenac with food. If you use an antacid (something to reduce acid in the stomach) you should avoid antacids with magnesium in them as these may make diarrhoea worse.
Common: may affect up to 1 in 10 people
· Rash, itching
· Vomiting, wind, constipation, burping, gastritis (indigestion, stomach ache, vomiting)
· Ulcers in the stomach or intestines
· Headache, dizziness
· Difficulty sleeping
· Changes in blood tests relating to the liver
· Inflammation of the digestive tract, including the intestines, such as nausea, diarrhoea, abdominal pain
· Abnormal formation of foetus
Uncommon: may affect up to 1 in 100 people
· Swelling of the mouth
· Fluid build-up in the body that can cause swollen ankles and legs
· Abnormal or unexpected bleeding from the vagina, menstrual disturbances
· Reduction in the number of blood platelets (increased chance of bleeding or bruising)
· Purpura (purple spots on the skin)
· Urticaria (raised itchy rash)
· Infection of the vagina (itching, burning, soreness, pain – especially during intercourse and/or urination)
· Blurred vision
· High blood pressure
· Loss of appetite
· Menstrual disorders such as usually heavy or light bleeding, or delayed periods
· Chills or fever
· Drowsiness, tiredness, feeling shaky
· Ringing in the ears
· Depression and feeling anxious
· Tingling or pricking (pins and needles)
· Mouth ulcers and dry mouth
Rare: may affect up to 1 in 1,000 people
· Inflammation of the liver (possible yellow discolouration of the skin, headache, fever, chills, general weakness)
· Inflammation of the pancreas, which causes severe pain in the abdomen and back
· Inflammation of the lungs, such as coughing, increased sputum
· Breast pain
· Vomiting blood
· Worsening of ulcerative colitis (inflammation of the lower intestine)
· Damage to the gullet
· Swelling of the tongue
· Low blood pressure
· Hair loss
· Increased sensitivity to light
· Nightmares
Very rare: may affect up to 1 in 10,000 people
· Severe liver disorders, including liver failure
Not known: frequency cannot be estimated from the available data
· Worsening of Crohn’s disease (inflammation of the intestines)
· Kidney problems
· Seizures
· Inflamed blood vessels (can cause fever, aches, purple blotches)
· Psychotic disorder (mental disorder that features loss of contact with reality)
· Mood swings, irritability, memory problems, feeling confused
· Difficulty seeing, changes in the way things taste
· Inflammation
· Abnormal contractions of the womb, rupture in the womb, retained placenta after giving birth, a life-threatening reaction in the mother due to the passage of amniotic fluid (fluid covering the foetus) or other foetal material into the maternal blood stream, bleeding in the womb, miscarriage, death of the unborn baby, premature birth
· Anaemia (low number of red blood cells) which can lead to pale skin and cause weakness or breathlessness
· Painful menstrual/period cramps
· Decreased fertility in females
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.
Reporting of suspected adverse reactions
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 (PvPI) by calling on 1800 180 3024 or report to Cipla Ltd on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.
· How should I store CIPZEN D PLUS 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.
CIPZEN D PLUS Tablets are a combination of diclofenac potassium, paracetamol and Serratiopeptidase. It is used for relieve symptoms such as fever, pain and inflammation associated with musculoskeletal and joint disorders.
Do not take this medicine if you
· have had an allergic reaction such as a skin rash, swelling or itchiness of the skin, severe nasal congestion, asthma or wheezing after taking diclofenac or other NSAIDs such as aspirin (acetylsalicylic acid);
· currently have an ulcer or perforation (hole) in your stomach or intestines;
· currently suffer from bleeding in your stomach, intestines or brain;
· are undergoing or you have just had coronary artery bypass graft (CABG) surgery;
· have severe kidney or liver failure;
· 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;
· have or have had problems with your blood circulation (peripheral arterial disease);
· have inflammation of the intestines (ulcerative colitis or Crohn’s disease);
· are dehydrated;
· are pregnant, or trying to become pregnant, because it may cause a miscarriage;
· are a woman of childbearing age and you are not using an effective contraceptive method to avoid becoming pregnant;
· are over the age of 65 years (your doctor will need to monitor you regularly); and/or,
· are taking other medicine containing paracetamol.
If you feel dizzy or drowsy after taking CIPZEN D PLUS Tablets, do not drive and do not use any tools or machines until these effects have worn off.
· What are the ingredients?
CIPZEN D PLUS Tablets contain diclofenac potassium 50 mg, paracetamol 325mg and Serratiopeptidase 10mg.
· 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), CIPZEN D PLUS 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
51/UA/SC/P-2013 Date: 02/02/2015
Date of Revision
10/01/2020