Pause D

Uses

Diclofenac Sodium ophthalmic preparation is used for-

• Inhibition of miosis during cataract surgery.
• Post-operative inflammation after cataract surgery and other ocular surgical procedures.
• Pre-operative and post-operative prevention of cystoid macular edema (CME) associated with lens extraction & intraocular lens implantation.
• Post-traumatic inflammation in penetrating and non- penetrating wounds (as an adjuvant to local anti-infective therapy).
• Non-infected chronic conjunctivitis, keratoconjunctivitis.

Haemorrhage or risk of haemorrhage in increased fibrinolysis or fibrinogenolysis that may occur in conditions:

• Prostatectomy and bladder surgery
• Menorrhagia
• Epistaxis
• Conisation of the cervix
• Management of dental extraction in patients with coagulopathies
• Ulcerative colitis
• Haematuria
• Gastrointestinal haemorrhage

General fibrinolysis as in prostatic and pancreatic cancer, after thoracic and other major surgery, in obstetrical complications such as abruptio placentae and post- partum haemorrhage, in leukaemia and liver diseases and in connection with thrombolytic therapy with streptokinase.

Hereditary angioneurotic oedema.

Pause D is also used to associated treatment for these conditions: Actinic Keratosis (AK), Acute Arthritis, Acute Gouty Arthritis, Acute Migraine, Acute Musculoskeletal Pain, Ankylosing Spondylitis (AS), Common Cold, Fever, Gouty Arthritis, Inflammation, Inflammatory Disease of the Oral Cavity, Inflammatory Disease of the throat, Inflammatory Reaction of the Nerve, Joint Pain, Juvenile Idiopathic Arthritis (JIA), Menstrual Distress (Dysmenorrhea), Muscle Inflammation, Ocular Inflammation, Operation site inflammation, Osteoarthritis (OA), Osteoarthritis of the Knee, Pain, Pain, Nerve, Pericarditis, Photophobia, Postoperative pain, Primary Dysmenorrhoea, Radicular Pain, Rheumatic Pain, Rheumatism, Rheumatoid Arthritis, Seasonal Allergic Conjunctivitis, Soreness, Muscle, Spinal pain, Tendon pain, Vertebral column pain, Acute Musculoskeletal injury, Acute, moderate, severe Pain, Inflammatory, Localized soft tissue rheumatism, Mild to moderate joint pain, Mild to moderate pain, Minor pain, Perioperative miosisBleeding, Heavy Menstrual Bleeding, Hereditary Angioedema

How Pause D works

Diclofenac inhibits cyclooxygenase-1 and -2, the enzymes responsible for production of prostaglandin (PG) G₂ which is the precursor to other PGs. These molecules have broad activity in pain and inflammation and the inhibition of their production is the common mechanism linking each effect of diclofenac.

PGE₂ is the primary PG involved in modulation of nociception. It mediates peripheral sensitization through a variety of effects. PGE₂ activates the G_q-coupled EP₁ receptor leading to increased activity of the inositol trisphosphate/phospholipase C pathway. Activation of this pathway releases intracellular stores of calcium which directly reduces action potential threshold and activates protein kinase C (PKC) which contributes to several indirect mechanisms. PGE₂ also activates the EP₄ receptor, coupled to G_s, which activates the adenylyl cyclase/protein kinase A (AC/PKA) signaling pathway. PKA and PKC both contribute to the potentiation of transient receptor potential cation channel subfamily V member 1 (TRPV1) potentiation, which increases sensitivity to heat stimuli. They also activate tetrodotoxin-resistant sodium channels and inhibit inward potassium currents. PKA further contributes to the activation of the P2X3 purine receptor and sensitization of T-type calcium channels. The activation and sensitization of depolarizing ion channels and inhibition of inward potassium currents serve to reduce the intensity of stimulus necessary to generate action potentials in nociceptive sensory afferents. PGE₂ act via EP₃ to increase sensitivity to bradykinin and via EP₂ to further increase heat sensitivity. Central sensitization occurs in the dorsal horn of the spinal cord and is mediated by the EP₂ receptor which couples to G_s. Pre-synaptically, this receptor increases the release of pro-nociceptive neurotransmitters glutamate, CGRP, and substance P. Post-synaptically it increases the activity of AMPA and NMDA receptors and produces inhibition of inhibitory glycinergic neurons. Together these lead to a reduced threshold of activating, allowing low intensity stimuli to generate pain signals. PGI₂ is known to play a role via its G_s-coupled IP receptor although the magnitude of its contribution varies. It has been proposed to be of greater importance in painful inflammatory conditions such as arthritis. By limiting sensitization, both peripheral and central, via these pathways NSAIDs can effectively reduce inflammatory pain.

PGI₂ and PGE₂ contribute to acute inflammation via their IP and EP₂ receptors. Similarly to β adrenergic receptors these are G_s-coupled and mediate vasodilation through the AC/PKA pathway. PGE₂ also contributes by increasing leukocyte adhesion to the endothelium and attracts the cells to the site of injury. PGD₂ plays a role in the activation of endothelial cell release of cytokines through its DP₁ receptor. PGI₂ and PGE₂ modulate T-helper cell activation and differentiation through IP, EP₂, and EP₄ receptors which is believed to be an important activity in the pathology of arthritic conditions. By limiting the production of these PGs at the site of injury, NSAIDs can reduce inflammation.

PGE₂ can cross the blood-brain barrier and act on excitatory G_q EP₃ receptors on thermoregulatory neurons in the hypothalamus. This activation triggers an increase in heat-generation and a reduction in heat-loss to produce a fever. NSAIDs prevent the generation of PGE₂ thereby reducing the activity of these neurons.

Tranexamic acid competitively and reversibly inhibits the activation of plasminogen via binding at several distinct sites, including four or five low-affinity sites and one high-affinity site, the latter of which is involved in its binding to fibrin. The binding of plasminogen to fibrin induces fibrinolysis - by occupying the necessary binding sites tranexamic acid prevents this dissolution of fibrin, thereby stabilizing the clot and preventing hemorrhage.

Dosage

Pause D dosage

Ophthalmic (Adult)-

• Postoperative ocular inflammation: Instill into the appropriate eye 4 times daily starting 24 hr after surgery for up to 28 days.
• Inflammation and discomfort after strabismus surgery: Instill 1 drop 4 times daily for the 1st wk; then tid in the 2nd wk, bid in the 3rd wk, and as required for the 4th wk.
• Pain and discomfort after radial keratotomy: Instill 1 drop before surgery followed by 1 drop immediately after surgery, and then 1 drop 4 times daily for up to 2 days.
• Pain after accidental trauma: Instill 1 drop 4 times daily for up to 2 days.
• Control of inflammation after argon laser trabeculoplasty:Instill 1 drop 4 times during the 2 hr before procedure followed by 1 drop 4 times daily, up to 7 days after procedure.
• Prophylaxis of intra-operative miosis: Instill into appropriate eye 4 times w/in 2 hr before surgery.
• Post-photorefractive keratectomy pain:Instill into the affected eye twice, an hr before surgery, then 1 drop twice at 5-min intervals immediately after surgery, then every 2-5 hr while awake for up to 24 hr.
• Seasonal allergic conjunctivitis:Instill 1 drop before surgery followed by 1 drop immediately after surgery, and then 1 drop 4 times daily for up to 2 days.

Intravenous administration is necessary only if it is difficult to give adequate doses by mouth. The recommended standard dose is 1 to 1.5 gm or 5-10 ml by slow intravenous injection at a rate of 1 ml/minute, two to three times daily. For the indications listed below the following doses are recommended.

PROSTATECTOMY: 5-10 ml by slow intravenous injection every eight hours (the first injection being given during the operation) for the first three days after surgery; thereafter 1-1.5 gm orally three to four times daily until macroscopic haematuria is no longer present.

MENORRHAGIA: 1-1.5 gm orally three to four times daily for three to four days.

EPISTAXIS: 1.5 gm orally three times daily for four to ten days.

Tranexamic Acid injection may be applied topically to the nasal mucosa of patients suffering from epistaxis. This can be done by soaking a gauze strip in the solution,and then packing the nasal cavity.

HAEMATURIA: 1-1.5 gm orally 2-3 times daily until macroscopic haematuria is no longer present.

CONISATION OF THE CERVIX: 1.5 gm orally 3 times a day for 12 to 14 days post-operatively.

DENTAL SURGERY IN PATIENTS WITH COAGULOPATHIES: Immediately before surgery, 10 mg per kg body-weight should be given intravenously. After surgery, 25 mg per kg body-weight are given orally three to four times daily for six to eight days. Coagulation factor concentrate might be necessary to administrate.

GENERAL FIBRINOLYSIS: 1 gm by slow intravenous injection three to four times daily. With fibrinolysis in conjunction with diagnosed, increased intravascular coagulation i.e. defibrillation syndrome, an anticoagulant such as heparin may be given with caution.

HEREDITARY ANGIONEUROTIC OEDEMA: 1-1.5 gm orally two to three times daily as intermittent or continuous treatment depending on whether the patient has prodromal symptoms or not.

CHILDREN:

• Oral dose: 25 mg/kg 2 to 3 times daily for 7 to 10 days.
• Injection: 10 mg/kg 6 to 8 hours for 7 to 10 days

Side Effects

Mild to moderate burning sensation in 5-15% patients which is transient in nature and almost never necessitated discontinuation of treatment. Other less common side-effects are sensitivity to light, bad taste, feeling of pressure, allergic reactions etc.

Dose-dependent, gastrointestinal discomfort is the most commonly reported undesirable effect, but it is usually of mild and temporary in nature. Allergic skin reactions have been reported as an uncommon undesirable effect. Hypotension may occur after fast injection.

Toxicity

Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain, and gastrointestinal bleeding. Hypertension, acute renal failure, respiratory depression and coma occur rarely. In case of overdose, provide supportive care and consider inducing emesis and administering activated charcoal if overdose occurred less than 4 hours prior.

Reported symptoms of tranexamic acid overdose include severe gastrointestinal symptoms, hypotension, thromboembolism, visual impairment, convulsions, mental status changes, and rash.

Precaution

Diclofenac eye drops may mask the signs of infection. So physicians should be alert to the development of infections in patients receiving the drug. During prolonged use, it is recommended that physicians conduct periodic examinations of the eye, including measurement of the intraocular pressure. Contact lenses should not be worn during treatment.

Patients with irregular menstrual bleeding, patients with a high risk of thrombosis (a previous thromboembolic event and a family history of thromboembolic disease) should use it only if there is a strong medical indication and under strict medical supervision.

Patients with disseminated intravascular coagulation (DIC), who require treatment with it must be under the strict supervision of a physician experienced in treating this disorder.

In the long-term treatment of patients, regular eye examination should be performed. If a colour vision disorder should occur during the course of treatment, the drug should be discontinued.

Interaction

No drug interaction is reported. There should be at least 5 minutes interval when another ophthalmic solution (e.g., steroid) is given.

Clinically important interactions have not been observed with Tranexamic acid. Because of the absence of interaction studies, simultaneous treatment with anticoagulants must take place under the strict supervision of a physician experienced in this field.

Volume of Distribution

Diclofenac has a total volume of distribution of 5-10 L or 0.1-0.2 L/kg. The volume of the central compartment is 0.04 L/kg. Diclofenac distributes to the synovial fluid reaching peak concentration 2-4h after administration. There is limited crossing of the blood brain barrier and cerebrospinal fluid concentrations only reach 8.22% of plasma concentrations. Doses of 50 mg delivered via intramuscular injection produced no detectable diclofenac concentrations in breast milk, however metabolite concentrations were not investigated. Diclofenac has been shown to cross the placenta in mice and rats but human data is unavailable.

The initial volume of distribution of tranexamic acid is 0.18 L/kg and its steady-state volume of distribution is 0.39 L/kg. Tranexamic acid distributes into cerebrospinal fluid and the aqueous humor of the eye at concentrations approximately 1/10th of typical plasma concentrations. Tranexamic acid is also able to cross the placenta, found in cord blood at concentrations equivalent to maternal plasma concentrations.

Elimination Route

Diclofenac is completely absorbed from the GI tract but likely undergoes significant first pass metabolism with only 60% of the drug reaching systemic circulation unchanged . Many topical formulations are absorbed percutaneous and produce clinically significant plasma concentrations. Absorption is dose proportional over the range of 25-150 mg. Tmax varies between formulations with the oral solution reaching peak plasma concentrations in 10-40min, the enteric coated tablet in 1.5-2h, and the sustained- and extended-release formulations prolonging Tmax even further. Administration with food has no significant effects on AUC but does delay Tmax to 2.5-12h.

The bioavailability of tranexamic acid after oral administration in humans is approximately 30 to 50% of the ingested dose and is not affected by food intake. The C_max and T_max following multiple oral doses (1300 mg three times daily x 5 days) were 16.41 mcg/mL and 2.5 h, respectively.

Half Life

The terminal half-life of diclofenac is approximately 2 h, however the apparent half-life including all metabolites is 25.8-33 h.

Following intravenous administration, the apparent elimination half-life is approximately 2 hours and the mean terminal half-life is approximately 11 hours.

Clearance

Diclofenac has a plasma clearance 16 L/h.

The plasma clearance of tranexamic acid is 110-116 mL/min.

Elimination Route

Diclofenac is mainly eliminated via metabolism. Of the total dose, 60-70% is eliminated in the urine and 30% is eliminated in the feces. No significant enterohepatic recycling occurs.

Urinary excretion is the primary means of tranexamic acid elimination, with >95% of an administered dose excreted in the urine as unchanged parent drug. The rate of excretion is dependent on the route of administration - approximately 90% of an intravenously administered dose is excreted within 24 hours whereas only 39% of an orally administered dose is excreted within the same time frame.

Pregnancy & Breastfeeding use

The safety of Diclofenac eye drops in pregnancy & lactation has not been established and its use therefore is not recommended unless the potential benefit to the mother outweighs the possible risk to the child.

Pregnancy: Tranexamic acid crosses the placenta. Clinical experience of use in pregnant women is limited. Animal studies have not supplied any evidence of an increased incidence of fetal damage.

Lactation: Tranexamic acid is excreted into breast milk, but it is not likely to influence the child at therapeutic doses.

Contraindication

Hypersensitivity to any of the components Like other non steroidal anti-inflammatory agents, Diclofenac Sodium eye drops is contraindicated in patients in whom attacks of asthma, urticaria or acute rhinitis have been observed following application of acetyl salicylic acid or other cyclo-oxygenase inhibitors

• Active thromboembolic disease, such as deep vein thrombosis, pulmonary embolism and cerebral thrombosis
• Subarachnoid haemorrhage
• Hypersensitivity to Tranexamic acid or any of the ingredients

Special Warning

Renal Impairment:

Intravenous : Adjust dose based on the serum-creatinine concentration:

• 120-250 micromol/l: 10 mg/kg bid daily;
• 250-500 micromoles/l: 10 mg/kg once daily;
• >500 micromol/l: 5 mg/kg once daily or 10 mg/kg once every 48 hr.

Oral : Adjust dose based on serum creatinine concentration:

• 120-250 micromol/l: 15 mg/kg bid daily;
• 250-500 micromol/l: 15 mg/kg once daily;
• >500 micromol/l: 7.5 mg/kg once daily or 15 mg/kg once every 48 hr.

Pediatric Use: The drug has had limited use in pediatric patients, principally in connection with tooth extraction. The limited data suggest that dosing instructions for adults can be used for pediatric patients needing Tranexamic acid therapy.

Geriatric Use: Clinical studies of Tranexamic acid did not include sufficient numbers of subjects aged 65 and over to determine whether they respond different y from younger subjects. Other reported clinical experien e has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Drug Interaction Tranexamic Acid is known to interact with other drugs like Factor VIII. These interactions are sometimes beneficial and sometimes may pose threats to life. Always consult your physician for the change of dose regimen or an alternative drug of choice that may strictly be required. Pharmaceutical Precaution Keep in a cool & dry place, protected from light. Keep out of the reach of children.

Acute Overdose

Accidental ingestion of Diclofenac Sodium presents virtually no risk of unwanted effects, since one 5 ml bottle of eye drop solution contains only 5 mg of Diclofenac Sodium, which is equivalent to about 3% of the recommended maximum oral dose for adults.

Symptoms: Nausea, vomiting, dizziness, and headache.

Treatment of overdose: If justified, initiate vomiting, then gastric lavage, charcoal therapy, and symptomatic treatment. Maintain adequate diuresis.

Storage Condition

Close the bottle immediately after use. Do not use for more than four weeks after opening. Store at room temperature.

Store at a cool and dry place, protected from light and moisture.

Innovators Monograph

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