Dolophob

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.

Heparin sodium is used for:

Atrial fibrillation with embolization:

• Treatment of acute and chronic consumption coagulopathies (disseminated intravascular coagulation);
• Prevention of clotting in arterial and heart surgery;
• Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its extension;
• (In a low-dose regimen) for prevention of postoperative deep venous thrombosis and pulmonary embolism in patients undergoing major abdomino-thoracic surgery or who for other reasons are at risk of developing thromboembolic disease
• Prophylaxis and treatment of pulmonary embolism;
• Prophylaxis and treatment of peripheral arterial embolism.

Dolophob 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 miosisBlunt Injuries, Clotting, Coagulopathy, Consumption, Contusions, Disseminated Intravascular Coagulation (DIC), External Hemorrhoid, Inflammation, Inflammatory, non-infectious pruritic dermatosis, Interstitial Cystitis, Pulmonary Embolism, ST Elevation Myocardial Infarction (STEMI), Sprains, Thromboembolism, Thrombosis, Venous, Unstable Angina Pectoris, Venous Thromboembolism, Embolization, Hematomas, Peripheral arterial embolism, Varicosities of the great saphenous vein, Maintenance of patency of IV injection devices

How Dolophob 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.

Under normal circumstances, antithrombin III (ATIII) inactivates thrombin (factor IIa) and factor Xa. This process occurs at a slow rate. Administered heparin binds reversibly to ATIII and leads to almost instantaneous inactivation of factors IIa and Xa The heparin-ATIII complex can also inactivate factors IX, XI, XII and plasmin. The mechanism of action of heparin is ATIII-dependent. It acts mainly by accelerating the rate of the neutralization of certain activated coagulation factors by antithrombin, but other mechanisms may also be involved. The antithrombotic effect of heparin is well correlated to the inhibition of factor Xa. Heparin is not a thrombolytic or fibrinolytic. It prevents progression of existing clots by inhibiting further clotting. The lysis of existing clots relies on endogenous thrombolytics.

Dosage

Dolophob 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-Prophylaxis of re-occlusion of the coronary arteries following thrombolytic therapy in myocardial infarction

• Adult: 60 U/kg (max: 4,000 U) or a bolus of 5,000 U if streptokinase was used, followed by 12 U/kg/hr (max: 1,000 U/hr) w/ a treatment duration of 48 hr.

Intravenous-

Peripheral arterial embolism, Unstable angina, Venous thromboembolism

• Adult: 75-80 U/kg or 5,000 U (10,000 U in severe pulmonary embolism) IV loading dose followed by 18 U/kg or 1,000-2,000 U/hr continuous infusion. Alternatively, intermittent inj of 5,000-10,000 U 4-6 hrly.
• Child: 50 U/kg loading dose, followed by an infusion of 15-25 U/kg/hr.
• Elderly: Lower dosages may be required.

Subcutaneous-

Prophylaxis of postoperative venous thromboembolism

• Adult: 5,000 U given 2 hr before surgery then 8-12 hrly for 7 days or until the patient is ambulant.

Subcutaneous-

Venous thromboembolism

• Adult: 15,000-20,000 U 12 hrly or 8,000-10,000 U 8 hrly.
• Child: 250 U/kg bid.
• Elderly: Lower dosages may be required.

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.

Hypersensitivity reactions (e.g. chills, fever, urticaria, asthma, rhinitis); painful, ischaemic and cyanosed limbs; osteoporosis (in long-term admin), suppression of aldosterone synthesis leading to hyperkalaemia, cutaneous necrosis, delayed transient alopecia, priapism, rebound hyperlipaemia; increased serum concentrations of AST and ALT, prolonged prothrombin time; local irritation, erythema, mild pain, haematoma or ulceration on inj site.

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.

In mouse, the median lethal dose is greater than 5000 mg/kg. Another side effect is heparin-induced thrombocytopenia (HIT syndrome). Platelet counts usually do not fall until between days 5 and 12 of heparin therapy. HIT is caused by an immunological reaction that makes platelets form clots within the blood vessels, thereby using up coagulation factors. It can progress to thrombotic complications such as arterial thrombosis, gangrene, stroke, myocardial infarction and disseminated intravascular coagulation. Symptoms of overdose may show excessive prolongation of aPTT or by bleeding, which may be internal or external, major or minor. Therapeutic doses of heparin give for at least 4 months have been associated with osteoporosis and spontaneous vertebral fractures. Osteoporosis may be reversible once heparin is discontinued. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., about 100–400 mg/kg daily) of benzyl alcohol in these neonates. Its use is principally associated with the use of bacteriostatic 0.9% sodium chloride intravascular flush or endotracheal tube lavage solutions.

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.

Patient with increased risk of bleeding complications, HTN, DM, pre-existing metabolic acidosis. Do not use in catheter lock flushing. Hepatic and renal impairment. Elderly. Pregnancy and lactation.

Interaction

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

Enhanced anticoagulant effect with other drugs affecting platelet function or the coagulation system (e.g. platelet aggregation inhibitors, thrombolytic agents, salicylates, NSAIDs, vit K antagonists, dextrans, activated protein C). Decreased anticoagulant effect with gyceryl trinitrate infusion. Increased risk of hyperkalaemia with ACE inhibitors or angiotensin II antagonists.

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.

40-70 mL/min (approximately the same as blood volume) Although heparin does not distribute into adipose tissues, clinicians should use actual body weight in obese patients to account for extra vasculature.

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.

Heparin must be given parenterally as it is not absorbed through the gastrointestinal mucosa. It is usually given by iv infusion or deep sc injection. The onset of action is immediate after iv injection but can be delayed 20 to 60 minutes following sc injection.

Plasma heparin concentrations may be increased and activated partial thromboplastin times (aPTTs) may be more prolonged in geriatric adults (older than 60 years of age) compared with younger adults.

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.

1.5 hours.

The plasma half-life of heparin increases from about 60 minutes with a 100 unit/kg dose to about 150 minutes with a 400 unit/kg dose.

Clearance

Diclofenac has a plasma clearance 16 L/h.

Adult Clearance = 0.43 ml/kg/min 25-28 weeks gestation = 1.49 ml/kg/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.

The drug appears to be removed mainly by the reticuloendothelial system. A small fraction of unchanged heparin also appears to be excreted in urine. Heparin cannot be eliminated by hemodialysis.

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 Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Nursing Mothers: Due to its large molecular weight, heparin is not likely to be excreted in human milk, and any heparin in milk would not be orally absorbed by a nursing infant. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant. Exercise caution when administering Heparin Sodium Injection to a nursing mother.

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

Current or history of heparin-induced thrombocytopenia; generalised or local haemorrhagic tendency, including uncontrolled severe HTN, severe liver insufficiency, active peptic ulcer, acute or subacute septic endocarditis, intracranial haemorrhage or injuries and operations on the CNS, eyes and ears, and in women with abortus imminens; epidural anaesth during birth; locoregional anaesth in elective surgical procedures (in patients receiving heparin for treatment rather than prophylaxis).

Special Warning

Pediatric Use: There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience. Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which vials have been confused with “catheter lock flush” vials

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: Bleeding (nose bleeds, blood in urine or tarry stools may be noted as the 1st sign of bleeding).

Management: May give protamine sulfate by slow IV infusion over 10 min to treat severe bleeding (1 mg of protamine sulfate neutralises approx 100 U of heparin). Max: 50 mg as a single dose.

Storage Condition

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

Store between 20-25° C. Protect from freezing.

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