Diclosef

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.

Famotidine is used for-

• Short term treatment of active duodenal ulcer and benign gastric ulcer
• Maintenance therapy for prevention of relapses of duodenal ulceration
• Gastro-oesophageal reflux disease
• Zollinger Ellison Syndrome

Diclosef 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 miosisChronic Back Pain, Duodenal Ulcer, Erosive Esophagitis, Extra-Articular Rheumatism, Gastritis, Heartburn, Helicobacter Pylori Infection, Multiple Endocrine Neoplasia, Muscle Spasms, Nonspecific Pain Post Traumatic Injury, Osteoarthritis (OA), Postoperative pain, Stress Ulcers, Zollinger-Ellison Syndrome, Active Gastric ulcer, Acute Duodenal Ulcers, Gastrointestinal ulceration, Pathological hypersecretory conditions, Symptomatic non-erosive gastroesphageal reflux disease

How Diclosef 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.

Histamine acts as a local hormone that stimulates the acid output by parietal cells via a paracrine mechanism. Neuroendocrine cells called enterochromaffin-like (ECL) cells lie close to the parietal cells and regulate the basal secretion of histamine. Histamine release is also promoted from stimulation by acetylcholine and gastrin, a peptide hormone. Gastrin (G) cells release gastrin, which works on CCK₂ receptors on ECL cells. This action promotes the release of histamine from ECL cells. Upon release, histamine acts on H₂ receptors expressed on the basolateral membrane of parietal cells, leading to increased intracellular cAMP levels and activated proton pumps on parietal cells. Proton pump releases more protons into the stomach, thereby increasing the secretion of acid. In conditions that are associated with acid hypersecretion such as ulcers, there is a loss of regulation of acid secretion. Famotidine works on H₂ receptors and blocks the actions of histamine.

Dosage

Diclosef 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.

Duodenal ulcer: 40 mg at night for 4 to 8 weeks

Benign gastric ulcer: 40 mg at night for 4 to 8 weeks; Maintenance therapy: 20 mg at night for preventing the recurrences of duodenal ulceration

Gastro-oesophageal reflux disease: 20 mg twice daily for 6 to 12 weeks

Zollinger Ellison syndrome: The recommended starting dose is 20 mg every six hours. Dosage should then be adjusted to individual response. Doses up to 160 mg every six hours have been administered to some patients without the development of significant adverse effects.

Dosage can be administered irrespective of meals. Antacids may be given concomitantly if needed.

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.

Famotidine is generally well tolerated and side effects are uncommon. Dizziness, headache, constipation and diarrhoea have been reported rarely. Other side effects reported less frequently include dry mouth, nausea and/or vomiting, rash, abdominal discomfort, anorexia and fatigue.

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.

The oral LD₅₀ is 4049 mg/kg in rats and 4686 mg/kg in mice. The subcutaneous LD₅₀ is 800 mg/kg in rats and mice. The lowest published toxic dose (TDLo) in man following oral administration is 4 mg/kg/7D.

Symptoms of overdose resemble the adverse events seen with the use of recommended doses, and they should be responded with supportive and symptomatic treatment. Any unabsorbed drug should be removed from the gastrointestinal tract, and the patient should be monitored accordingly. The use of hemodialysis to eliminate the drug from the systemic circulation is effective, but the experience of using hemodialysis in response to famotidine overdose is limited in clinical settings.

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.

Dosage reduction should be considered or interval between doses should be prolonged if creatinine clearance falls to or below 30 ml/min.

Interaction

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

Famotidine does not interact with the cytochrome P450 linked drug metabolising enzyme system. So, no interactions have been found in man with Warfarin, Theophylline, Phenytoin, Diazepam, Propranolol, Aminopyrine or antipyrine.

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 steady-state volume of distribution ranges from 1.0 to 1.3 L/kg. Famotidine is found in breast milk; however, it is found in breast milk at the lowest concentrations compared to other H₂ receptor antagonists.

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.

Following oral administration, the absorption of famotidine is dose-dependent and incomplete. The oral bioavailability ranges from 40-50%, and the Cmax is reached in 1-4 hours post-dosing. While the bioavailability can be slightly increased with the intake of food and decreased by antacids, there is no clinical significance.

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.

The elimination half-life is about 2 to 4 hours. The half-life is expected to increase nonlinearly in patients with decreased renal function.

Clearance

Diclofenac has a plasma clearance 16 L/h.

Renal clearance is 250-450 mL/min, indicating some tubular excretion. Because the renal clearance rate exceeds the glomerular filtration rate, famotidine is thought to be mainly eliminated via both glomerular filtration and renal tubular secretion.

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.

About 65-70% of the total administered dose of famotidine undergoes renal elimination, and 30-35% of the dose is cleared by metabolism. Following intravenous administration, about 70% of the drug is eliminated in the urine as an unchanged drug.

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: There are no adequate, well controlled studies on Famotidine in pregnancy, but it is known to cross the placenta and should be prescribed only if clearly needed.

Lactation: It is not known whether Famotidine is secreted into human milk, nursing mothers should either stop nursing or stop taking the drug.

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

There are no known contraindication to Famotidine. If any evidence of hypersensitivity appear, the therapy should be discontinued and consultation with physician is required.

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.

Storage Condition

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

Tablet: Store between 15-30° C. Concentrate for injection: Store between 2-8° C.

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