Diclofenac sodium Ampoules USP 75mg Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT
Diclofenac sodium Ampoules USP 75mg Taj Pharma.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
The active ingredient is sodium-[o-[(2,6-dichlorophenyl)-amino]-phenyl]-acetate) (diclofenac sodium).

Each 3ml ampoule contains
Diclofenac sodium USP          75mg
Water for Injection                    q.s.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Solution for injection in ampoules.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Ampoules for im use:

The ampoules are effective in acute forms of pain, including renal colic, exacerbations of osteo- and rheumatoid arthritis, acute back pain, acute gout, acute trauma and fractures, and post-operative pain.

Ampoules used in intravenous infusion:

For treatment or prevention of post-operative pain in the hospital setting.

4.2  Posology and method of administration
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4 Special warnings and precautions for use).

Adults
Diclofenac sodium ampoules (given im or iv) should not be given for more than two days; if necessary, treatment can be continued with Diclofenac sodium tablets or suppositories.

Intramuscular injection: The following directions for intramuscular injection must be adhered to in order to avoid damage to a nerve or other tissue at the injection site.

One ampoule once (or in severe cases twice) daily intramuscularly by deep intragluteal injection into the upper outer quadrant. If two injections daily are required it is advised that the alternative buttock be used for the second injection. Alternatively, one ampoule of 75mg can be combined with other dosage forms of Diclofenac sodium (tablets or suppositories) up to the maximum daily dosage of 150mg.

Renal colic: One 75mg ampoule intramuscularly. A further ampoule may be administered after 30 minutes if necessary. The recommended maximum daily dose of Diclofenac sodium is 150mg.

Intravenous Infusion: Immediately before initiating an intravenous infusion, Diclofenac sodium must be diluted with 100-500ml of either sodium chloride solution (0.9%) or glucose solution (5%). Both solutions should be buffered with sodium bicarbonate solution (0.5ml 8.4% or 1ml 4.2%). Only clear solutions should be used.

Diclofenac sodium must not be given as an intravenous bolus injection.

Two alternative regimens are recommended:

For the treatment of moderate to severe post-operative pain, 75mg should be infused continuously over a period of 30 minutes to 2 hours. If necessary, treatment may be repeated after 4-6 hours, not exceeding 150mg within any period of 24 hours.

For the prevention of post-operative pain, a loading dose of 25mg-50mg should be infused after surgery over 15 minutes to 1 hour, followed by a continuous infusion of approx. 5mg per hour up to a maximum daily dosage of 150mg.

Special populations

Elderly
Although the pharmacokinetics of Diclofenac sodium are not impaired to any clinically relevant extent in elderly patients, nonsteroidal anti-inflammatory drugs should be used with particular caution in such patients who generally are more prone to adverse reactions. In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight (see also Precautions) and the patient should be monitored for GI bleeding during NSAID therapy.

Cardiovascular and significant cardiovascular risk factors
Diclofenac is contraindicated in patients with established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease (see section 4.3 Contraindications).

Patients with congestive heart failure (NYHA-I) or significant risk factors for cardiovascular disease should be treated with diclofenac only after careful consideration. Since cardiovascular risks with diclofenac may increase with dose and duration of exposure, the lowest effective daily dose should be used and for the shortest duration possible (see section 4.4 Special warnings and precautions for use).

Renal impairment
Diclofenac is contraindicated in patients with renal failure (see section 4.3 Contraindications).

No specific studies have been carried out in patients with renal impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering diclofenac to patients with mild to moderate renal impairment (see section 4.4 Special warnings and precautions for use).

Hepatic impairment
Diclofenac is contraindicated in patients with hepatic failure (see section 4.3 Contraindications).

No specific studies have been carried out in patients with hepatic impairment, therefore, no specific dose adjustment recommendations can be made. Caution is advised when administering diclofenac to patients with mild to moderate hepatic impairment (see section 4.4 Special warnings and precautions for use).

Paediatric population
Diclofenac sodium ampoules are not recommended for use in children.

The recommended maximum daily dose of Diclofenac sodium is 150mg.

4.3 Contraindications
• Hypersensitivity to the active substance, sodium metabisulphite or any of the excipients.

  • Active, gastric or intestinal ulcer, bleeding or perforation
  • History of gastrointestinal bleeding or perforation, relating to previous NSAID therapy
  • Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding)
  • Last trimester of pregnancy (see section 4.6 Pregnancy and lactation)
  • Hepatic failure
  • Renal failure
  • Established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease
  • Like other non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac is also contraindicated in patients in whom attacks of asthma, angioedema, urticaria or acute rhinitis are precipitated by ibuprofen, acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.

Specifically for iv use.

  • Concomitant NSAID or anticoagulant use (including low dose heparin).
  • History of haemorrhagic diathesis, a history of confirmed or suspected cerebrovascular bleeding.
  • Operations associated with a high risk of haemorrhage.
  • A history of asthma.
  • Moderate or severe renal impairment (serum creatinine >160μmol/l).
  • Hypovolaemia or dehydration from any cause.

4.4 Special Warnings and precautions for use
General
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 Posology and method of administration and GI and cardiovascular risks below.)

The concomitant use of Diclofenac sodium with systemic 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 (see section 4.5 Interactions with other medicaments and other forms of interaction).

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 (see section 4.2 Posology and Method of administration).

As with other nonsteroidal anti-inflammatory drugs including diclofenac, allergic reactions, including anaphylactic/anaphylactoid reactions can also occur without earlier exposure to the drug (see section 4.8 Undesirable effects). 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 may mask the signs and symptoms of the infection due to its pharmacodynamic properties.

The sodium metabisulphite present in solution for injection can also lead to isolated severe hypersensitivity reactions and bronchospasm.

The instructions for intramuscular injection should be strictly followed in order to avoid adverse events at the injection site, which may result in muscle weakness, muscle paralysis, hypoaesthesia and injection site necrosis.

Gastrointestinal effects:
Gastrointestinal bleeding (haematemesis, melaena), ulceration or perforation which can be fatal has been reported with all NSAIDs including diclofenac and may occur 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. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be withdrawn.

As with all NSAIDsincluding diclofenacclose medical surveillance is imperative and particular caution should be exercised when prescribing diclofenac in patients with symptoms indicative of gastrointestinal disorders, or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see section 4.8 Undesirable effects). The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses including diclofenac, and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation.

The elderly have increased frequency of adverse reactions to NSAIDs especially gastro intestinal bleeding and perforation which may be fatal (see section 4.2 Posology and method of administration).

To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly, the treatment should be initiated and maintained at the lowest effective dose.

Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low dose acetylsalicylic acid (ASA/aspirin or medicinal products likely to increase gastrointestinal risk. (See section 4.5 Interactions with other medicaments and other forms of interaction).

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding).

Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents such as acetylsalicylic acid (see section 4.5 Interaction with other medicaments and other forms of interaction).

Close medical surveillance and caution should be exercised in patients with ulcerative colitis, or with Crohn’s disease as these conditions may be exacerbated (see section 4.8 Undesirable effects).

NSAIDs, including diclofenac, may be associated with increased risk of gastro-intestinal anastomotic leak. Close medical surveillance and caution are recommended when using diclofenac after gastro-intestinal surgery.

Hepatic effects:
Close medical surveillance is required when prescribing Diclofenac sodium 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 sodium should be discontinued.

Hepatitis may occur with diclofenac without prodromal symptoms.

Caution is called for when using diclofenac in patients with hepatic porphyria, since it may trigger an attack.

Renal effects:
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 (see section 4.3 Contraindications). 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.

Skin effects:
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, including Diclofenac sodium (see section 4.8 Undesirable effects). Patients appear to be at the highest risk of 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 sodium should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of
hypersensitivity.

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 (see section 4.8 Undesirable effects).

Cardiovascular and cerebrovascular effects:
Patients with congestive heart failure (NYHA-I) or patients with significant risk factors for cardiovascular events (e.g. hypertension, 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.

Appropriate monitoring and advice are required for patients with a history of hypertension and congestive heart failure (NYHA-I) as fluid retention and oedema have been reported in association with NSAID therapy including diclofenac.

Clinical trial and epidemiological data consistently point towards 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.

Patients should remain alert for the signs and symptoms of serious arteriothrombotic events (e.g. chest pain, shortness of breath, weakness, slurring of speech), which can occur without warnings. Patients should be instructed to see a physician immediately in case of such an event.

Haematological effects:
During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended.

Diclofenac sodium may reversibly inhibit platelet aggregation (see anticoagulants in section 4.5 Interaction with other medicaments and other forms of interactions). Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

Pre-existing asthma:
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 sodium and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of bronchial asthma.

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 (see section 4.6 Pregnancy and Lactation).

4.5 Interaction with other medicinal products and other forms of interaction
The following interactions include those observed with diclofenac gastro-resistant tablets and/or other pharmaceutical forms of diclofenac.

Lithium: If used concomitantly, Diclofenac sodium may increase plasma concentrations of lithium Monitoring of the serum lithium level is recommended.

Digoxin: If used concomitantly, Diclofenac sodium may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.

Diuretics and antihypertensive agents: Like other NSAIDs, concomitant use of Diclofenac sodium 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.

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 (see section 4.4 Special warnings and precautions for use).

Anticoagulants and anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding (see section 4.4 Special warnings and precautions for use). 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 (see section 4.4 Special warnings and precautions for use). 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.

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 (see section 4.4 Special warnings and precautions for use).

Selective serotonin reuptake inhibitors (SSRIs): Concomitant administration of SSRI’s may increase the risk of gastrointestinal bleeding (see section 4.4 Special warnings and precautions for use).

Antidiabetics: Clinical studies have shown that Diclofenac sodium can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

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.

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.

Cardiac glycosides: Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

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.

4.6 Fertility, Pregnancy and lactation
Pregnancy
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. If Diclofenac sodium is used by a woman attempting to conceive, or during the 1st trimester 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 sodium is contra-indicated during the third trimester of pregnancy.

Lactation
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 (see section 5.2 Pharmacokinetic properties).

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 may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac should be considered. See also section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7 Effects on ability to drive and use machines
Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disturbances, drowsiness or fatigue while taking NSAIDs should refrain from driving or operating machinery.

4.8 Undesirable Effects
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); not known: cannot be estimated from available data.

The following undesirable effects include those reported with other short-term or long-term use.

Table 1

Infection and Infestations
Unknown Injection site necrosis.
Blood and lymphatic system disorders
Very rare Thrombocytopenia, leucopoenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.
Immune system disorders
Rare

Very rare

Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).

Angioneurotic oedema (including face oedema).

Psychiatric disorders
Very rare Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.
Nervous system disorders
Common

Rare

Very rare

Unknown

Headache, dizziness.

Somnolence, tiredness.

Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident.

Confusion, hallucinations, disturbances of sensation, malaise.

Eye disorders
Very rare

Unknown

Visual disturbance, vision blurred, diplopia.

Optic neuritis.

Ear and labyrinth disorders
Common

Very rare

Vertigo.

Tinnitus, hearing impaired.

Cardiac disorders
Uncommon* Myocardial infarction, cardiac failure, palpitations, chest pain.
Not known Kounis syndrome.
Vascular disorders
Very rare Hypertension, hypotension, vasculitis.
Respiratory, thoracic and mediastinal disorders
Rare

Very rare

Asthma (including dyspnoea).

Pneumonitis.

Gastrointestinal disorders
Common

Rare

 

 

Very rare

 

 

Unknown

Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia.

Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer with or without bleeding or perforation (sometimes fatal particularly in the elderly).

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.

Ischaemic colitis.

Hepatobiliary disorders
Common

Rare

Very rare

Transaminases increased.

Hepatitis, jaundice, liver disorder.

Fulminant hepatitis, hepatic necrosis, hepatic failure.

Skin and subcutaneous tissue disorders
Common

Rare

Very rare

Rash.

Urticaria.

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.
Reproductive system and breast disorders
Very rare Impotence.
General disorders and administration site conditions
Common

Rare

Injection site reaction, injection site pain, injection site induration.

Oedema.

* The frequency reflects data from long-term treatment with a high dose (150 mg/day).

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 doses (150mg daily) and in long term treatment (see sections 4.3 and 4.4 for Contraindications and Special warnings and special precautions for use).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose
Symptoms
There is no typical clinical picture resulting from diclofenac over dosage. Over dosage can cause symptoms such as headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, diarrhoea, dizziness, disorientation, excitation, coma, drowsiness, tinnitus, fainting or convulsions. In the case of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measures
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 potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patients clinical condition.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action
Diclofenac sodium is a nonsteroidal agent with marked analgesic/anti- inflammatory properties. It is an inhibitor of prostaglandin synthetase, (cyclo-oxygenase). Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings. When used concomitantly with opioids for the management of post-operative pain, Diclofenac sodium often reduces the need for opioids.

5.2 Pharmacokinetic properties
Absorption
After administration of 75mg diclofenac by intramuscular injection, absorption sets in immediately, and mean peak plasma concentrations of about 2.558 ± 0.968µg/ml (2.5µg/mL ≡ 8µmol/L) are reached after about 20 minutes. The amount absorbed is in linear proportion to the size of the dose.

Intravenous infusion: When 75mg diclofenac is administered as an intravenous infusion over 2 hours, mean peak plasma concentrations are about 1.875 ± 0.436µg/ml (1.9µg/mL ≡ 5.9µmol/L). Shorter infusions result in higher peak plasma concentrations, while longer infusions give plateau concentrations proportional to the infusion rate after 3 to 4 hours. This is in contrast to the rapid decline in plasma concentrations seen after peak levels have been achieved with oral, rectal or i.m. administration.

Bioavailability:
The area under the concentration curve (AUC) after intramuscular or intravenous administration is about twice as large as it is following oral or rectal administration as this route avoids “first-pass” metabolism.

Distribution
The active substance is 99.7% protein bound, mainly to albumin (99.4%).
Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hours after the peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 hours. Two hours after reaching the peak plasma values, concentrations of the active substance are already higher in the synovial fluid than they are in the plasma and remain higher for up to 12 hours.

Diclofenac was detected in a low concentration (100 ng/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 (see section 4.6 Pregnancy and lactation).

Metabolism
Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

Elimination
Total systemic clearance of diclofenac in plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours.

About 60% of the administered dose is excreted in the urine in the form of the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.

Characteristics in patients
Elderly: No relevant age-dependent differences in the drug’s absorption, metabolism or excretion have been observed, other than the finding that in five elderly patients, a 15 minute iv infusion resulted in 50% higher plasma concentrations than expected with young healthy subjects.

Patients with renal impairment: 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 calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.

Patients with hepatic disease: In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

5.3 Preclinical safety data
None stated.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Diclofenac sodium ampoules also contain mannitol, sodium metabisulphite (E.223), benzyl alcohol, propylene glycol, sodium hydroxide and water.

6.2 Incompatibilities
The ampoules used im or iv as an infusion should not be mixed with other injection solutions.

6.3  Shelf life
Two years.

6.4 Special precautions for storage
Protect from light and heat (store below 30°C).
Medicines should be kept out of the reach of children.
The infusion solution should not be used if crystals or precipitates are observed.

6.5 Nature and contents of container
The glass ampoules (Ph.Eur. Type I) contain colourless to faintly yellow liquid and come in packs of 2 and 10.

6.6 Special precautions for disposal and other handling
Intravenous infusions should be freshly made up and used immediately. Once prepared, the infusion should not be stored.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Diclofenac sodium Ampoules USP 75mg Taj Pharma

Package leaflet: Information for the patient

Diclofenac sodium Ampoules USP 75mg Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
 – If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

What is in this leaflet
1. What  Diclofenac sodium Ampoules is and what it is used for
2. Before you are given Diclofenac sodium Ampoules
3. How you will be given  Diclofenac sodium Ampoules
4. Possible side effects
5. How Diclofenac sodium Ampoules is stored
6. Further Information

1. What Diclofenac sodium Ampoules is and what it is used for
Diclofenac sodium, the active ingredient in Diclofenac sodium Ampoules, is one of a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs reduce pain and inflammation.

The intramuscular injection is used to treat a number of painful conditions including:
• ‘Flare-ups’ of joint or back pain
• Attacks of gout
• Pain caused by kidney stones
• Pain caused by injuries.

Diclofenac sodium Ampoules can either be given as an injection into the muscle, or as a slow infusion into a vein. The intravenous infusion is used in hospitals to prevent or treat pain following an operation.

Diclofenac sodium Ampoules are not suitable for children.

2. Before you are given Diclofenac sodium Ampoules
Some people MUST NOT have this injection. Talk to your doctor if:
• you think you may be allergic to diclofenac sodium, sodium metabisulphite, aspirin, ibuprofen or any other NSAID, or to any of the other ingredients of Diclofenac sodium Ampoules. (These are listed at the end of the leaflet.) 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 heart, kidney or liver failure
• if 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 bypass blockages
• if you have or have had problems with your blood circulation (peripheral arterial disease)
• you are more than six months pregnant

You should also ask yourself these questions before having a Diclofenac sodium Injection or Infusion:
• Do you suffer from any bowel disorders including ulcerative colitis or Crohn’s disease?
• Do you have kidney or liver problems, or are you elderly?
• Do you suffer from any blood or bleeding disorder?
• Do you have a condition called porphyria?
• Have you ever had asthma?
• Are you breastfeeding?
• Do you have angina, blood clots, high blood pressure, abnormally high levels of fat in your blood (raised cholesterol or raised triglycerides)?
• Do you have heart problems, or have you had a stroke, or do you think you might be at risk of these conditions (for example, if you have high blood pressure, diabetes or high cholesterol or are a smoker)?
• Do you have diabetes?
• Do you smoke?
• Do you have Lupus (SLE) or any similar condition?
• Could you be suffering from dehydration?
• Have you suffered any heavy loss of blood recently?

If the answer to any of these questions is YES, discuss your treatment with your doctor or pharmacist because Diclofenac sodium Ampoules might not be the right medicine for you.

Are you taking other medicines?
Some medicines can interfere with your treatment. Tell your doctor or pharmacist if you are taking any of the following:
• Medicines to treat diabetes
• Anticoagulants (blood thinning tablets like warfarin)
• Diuretics (water tablets)
• Lithium (used to treat some mental problems)
• Methotrexate (for some inflammatory diseases and some cancers)
• Ciclosporin and tacrolimus (used to treat some inflammatory diseases and after transplants)
• Trimethoprim (a medicine used to prevent or treat urinary tract infections)
• Quinolone antibiotics (for infections)
• Any other NSAID or COX-2 (cyclo-oxgenase-2) inhibitor, for example aspirin or ibuprofen
• Mifepristone (a medicine used to terminate pregnancy)
• Cardiac glycosides (for example digoxin), used to treat heart problems
• Medicines known as SSRIs used to treat depression
• Oral steroids (an anti-inflammatory drug)
• Medicines used to treat heart conditions or high blood pressure, for example beta-blockers or ACE inhibitors.
• Voriconazole (a medicine used to treat fungal infections).
• Phenytoin (a medicine used to treat seizures)
• Colestipol/cholestyramine (used to lower cholesterol)

Always tell your doctor or pharmacist about all the medicines you are taking. This means medicines you have bought yourself as well as medicines on prescription from your doctor.

Pregnancy
• Are you pregnant or planning to become pregnant? Although not common, abnormalities have been reported in babies whose mothers have taken NSAIDs during pregnancy. You should not have a Diclofenac sodium Injection during the last 3 months of pregnancy as it may affect the baby’s circulation.
• Are you trying for a baby? Having Diclofenac sodium Injections may make it more difficult to conceive. You should talk to your doctor if you are planning to become pregnant, or if you have problems getting pregnant.

Will there be any problems with driving or using machinery?
Very occasionally people have reported that Diclofenac sodium Ampoules have made them feel dizzy, tired or sleepy. Problems with eyesight have also been reported. If you are affected in this way, you should not drive or operate machinery.

Other special warnings
• You should take the lowest dose of Diclofenac sodium for the shortest possible time, particularly if you are underweight or elderly.
• There is a small increased risk of heart attack or stroke when you are taking any medicine like Diclofenac sodium. The risk is higher if you are taking high doses for a long time. Always follow the doctor’s instructions on how much to take and how long to take it for.
• If at any time while taking Diclofenac sodium you experience any signs or symptoms of problems with your heart or blood vessels such as chest pain, shortness of breath, weakness, or slurring of speech, contact your doctor immediately.
• Whilst you are taking these medicines your doctor may want to give you a check-up from time to time.
• If you have a history of stomach problems when you are taking NSAIDs, particularly if you are elderly, you must tell your doctor straight away if you notice any unusual symptoms.
• Because it is an anti-inflammatory medicine, Diclofenac sodium may reduce the symptoms of infection, for example, headache and high temperature. If you feel unwell and need to see a doctor, remember to tell him or her that you are taking Diclofenac sodium.
• Diclofenac sodium Ampoules contain the preservative, sodium metabisulphite. This can sometimes cause allergic reactions and breathing difficulties.
• Diclofenac sodium Ampoules should not be used in children.

Tell your doctor if you recently had or you are going to have a surgery of the stomach or intestinal tract before taking Diclofenac sodium Ampoules, as Diclofenac sodium Ampoules can sometimes worsen wound healing in your gut after surgery.

3. How you will be given Diclofenac sodium Ampoules
Your doctor will decide when and how to treat you with Diclofenac sodium Ampoules. You will either be given an intravenous infusion (a drip into a vein) or an intramuscular injection (an injection into a muscle). The intramuscular injection is usually injected into the buttocks.

The usual dose is:
Adults
One or two ampoules (75 to 150 mg) each day for one or two days.

Elderly
Your doctor may give you a dose that is lower than the usual adult dose if you are elderly.

Children
Not suitable for children.

A doctor, nurse or pharmacist will prepare the injection for you.
If you have had an operation and are in hospital, the ampoule contents may be diluted and put into a drip bag before being given to you. A nurse or doctor will usually then give you the injection or infusion. You would not usually have to give the injection to yourself.

The doctor may also prescribe another drug to protect the stomach to be taken at the same time, particularly if you have had stomach problems before, or if you are elderly, or taking certain other drugs as well.

What if you have had too much Diclofenac sodium? (Overdose)
If you think you have been given too much Diclofenac sodium tell your doctor or nurse straight away.

4. Possible Side Effects
Diclofenac sodium Ampoules are suitable for most people, but, like all medicines, they can sometimes cause side effects. Side effects may be minimised by using the lowest effective dose for the shortest duration necessary.

Some side effects can be serious
Tell the doctor straight away if you notice:

• Sudden and crushing chest pain (signs of myocardial infarction or heart attack)
• Breathlessness, difficulty breathing when lying down, swelling of the feet or legs (signs of heart failure)
• Sudden weakness or numbness in the face, arm or leg especially on one side of the body; sudden loss or disturbance of vision; sudden difficulty in speaking or ability to understand speech; sudden migraine-like headaches which happen for the first time, with or without disturbed vision. These symptoms can be an early sign of a stroke.
• Stomach pain, indigestion, heartburn, wind, nausea (feeling sick) or vomiting (being sick)
• Any sign of bleeding in the stomach or intestine, for example, 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 Diclofenac sodium Ampoules and followed by rectal bleeding or bloody diarrhoea usually within 24 hours of the onset of abdominal pain.
• 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 side effects (These may affect between 1 and 10 in every 100 patients):
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
Injection site reactions, symptoms include redness, swelling, change in the skin colour, inflammation, pain, and hypersensitivity.

Uncommon side effects (These may affect between 1 and 10 in every 1000 patients):
Fast or irregular heart beat (palpitations), chest pain, heart disorders, including heart attack or breathlessness, difficulty breathing when lying down, or swelling of the feet or legs (signs of heart failure), especially if you have been taking a higher dose (150 mg per day) for a long period of time.

Rare side effects (These may affect between 1 in every 1000 to 1 in every 10,000 patients):
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
Skin rash and itching
Fluid retention, symptoms of which include swollen ankles
Liver function disorders, including hepatitis and jaundice
Asthma (symptoms may include wheezing, breathlessness, coughing and a tightness across the chest)
Injection site necrosis (dead skin and tissue around the injection site).

Very rare side effects (These may affect less than 1 in every 10,000 patients):
Effects on the nervous system:
Inflammation of the lining of the brain (meningitis), tingling or numbness in the fingers, tremor, visual disturbances such as blurred or double vision, taste changes, hearing loss or impairment, tinnitus (ringing in the ears), sleeplessness, nightmares, mood changes, depression, anxiety, irritability, mental disorders, disorientation and loss of memory, fits, headaches together with a dislike of bright lights, fever and a stiff neck.

Effects on the stomach and digestive system:
Constipation, inflammation of the tongue, mouth ulcers, inflammation of the inside of the mouth or lips, lower gut disorders (including inflammation of the colon, or worsening of colitis or Crohn’s disease), inflammation of the pancreas.

Effects on the chest or blood:
Hypertension (high blood pressure), hypotension (low blood pressure, symptoms of which may include faintness, giddiness or light headedness), inflammation of blood vessels (vasculitis), inflammation of the lung (pneumonitis), 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:
Facial swelling, 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.

Effects on the reproductive system:
Impotence.

Other side effects that have also been reported with unknown frequency include:
Injection site abscess, hroat disorders, confusion, hallucinations, malaise (general feeling of discomfort), inflammation of the nerves in the eye, disturbances of sensation, tissue damage at the injection site.

Do not be alarmed by this list – most people have an injection of Diclofenac sodium without any problems.

Reporting of side effects
If you get any side effects, talk your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How Diclofenac sodium Ampoules is stored
Store below 30°C. Protect from light and heat.
Keep out of the reach and sight of children.
Do not use Diclofenac sodium Ampoules after the expiry date which is printed on the outside of the pack.

6. Further information
The active ingredient is diclofenac sodium, in solution.

Each 3ml ampoule contains
Diclofenac sodium USP     75mg
Water for Injection          q.s.

The ampoules also contain mannitol, sodium metabisulphite (E223), benzyl alcohol, propylene glycol, sodium hydroxide, water.

Diclofenac sodium Ampoules come in packs of 10.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com