Dufex

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.

Pantoprazole is used where suppression of acid secretion is of therapeutic benefit. Pantoprazole Is registered in the foltawing indications:

• Peptic ulcer diseases (PUD)
• Gastro-esophageal reflux diseases
• Treatment of ulcer resistant to M2 blocker
• Treatment of ulcer induced by NSAIDs
• Gl bleeding from stress or acid peptic diseases
• Eradication of Helicobacter pylori
• Zollinger-Ellison syndrome
• Prophylaxis for acid aspiration syndrome during induction of anesthesia

Dufex 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 miosisErosive Esophagitis, GERD With Erosive Esophagitis, Gastro-esophageal Reflux Disease (GERD), Healing, Heartburn, Helicobacter Pylori Infection, Stress Ulcers, Zollinger-Ellison Syndrome, Conditions where a reduction of gastric acid secretion is required, Pathological hypersecretory conditions

How Dufex 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.

Hydrochloric acid (HCl) secretion into the gastric lumen is a process regulated mainly by the H(+)/K(+)-ATPase of the proton pump, expressed in high quantities by the parietal cells of the stomach. ATPase is an enzyme on the parietal cell membrane that facilitates hydrogen and potassium exchange through the cell, which normally results in the extrusion of potassium and formation of HCl (gastric acid).

Proton pump inhibitors such as pantoprazole are substituted benzimidazole derivatives, weak bases, which accumulate in the acidic space of the parietal cell before being converted in the canaliculi (small canal) of the gastric parietal cell, an acidic environment, to active sulfenamide derivatives. This active form then makes disulfide bonds with important cysteines on the gastric acid pump, inhibiting its function. Specifically, pantoprazole binds to the sulfhydryl group of H+, K+-ATPase, which is an enzyme implicated in accelerating the final step in the acid secretion pathway. The enzyme is inactivated, inhibiting gastric acid secretion. The inhibition of gastric acid secretion is stronger with proton pump inhibitors such as pantoprazole and lasts longer than with the H(2) antagonists.

Dosage

Dufex 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.

Tablet:

The usual recommended adult oral dose is 40 mg given once daily, preferably in the morning with or without food. The duration of therapy is ranging from 2-8 weeks.

• Duodenal ulcers: Pantoprazole 40 mg tablet once daily for 2-4 weeks.
• Gastric ulcer: Pantoprazole 40 mg tablet once daily for 4-8 weeks.
• Reflux esophagitis: Pantoprazole 40 mg tabletonce daily for 4-8 weeks.
• Ulcers induced by NSAIDs: Pantoprazole 40 mg tablet once daily.
• Maintenance therapy: Maintenance therapy should involve the lowest effective dose of the drug. Pantoprazole both 20 mg & 40 mg doses are safe and effective in maintaining patients with healed reflux esophagitis and PUD in remission.

IV Injection:

• Duodenal ulcer and gastric ulcer:40 mg once daily for 7-10 days
• Gastroesophageal reflux disease associatedwith a history of erosive esophagitis:40 mg once daily for 7-10 days
• Prevention of rebleeding in peptic ulcer:IV 80 mg, followed by 8 mg/hour infusion for 72 hours
• Prophylaxis of acid aspiration:80 mg IV every 12 h for 24 h, followed by 40mg every 12 h
• Long-term management of Zollinger-Ellison Syndrome and other pathological hypersecretory conditions: 80 mg IV every 12 hours, may increase to 80 mg every 8 hoursif needed, may titrate to higher doses depending on acid output.

DIRECTION FOR USE OF IV INJECTION: Pantoprazole lyophilized powder and 0.9% Sodium Chloride Injection is for intravenous administration only and must not be given by any other route. Pantoprazole IV injection should be given as a slow intravenous injection. The solution for IV injection is obtained by adding 10 ml 0.9% Sodium Chloride Injection to the vial containing powder. After reconstitution the injection should be given slowly over a period of at least 2 to 5 minutes. Use only freshly prepared solution. The reconstituted solution may be stored at room temperature (up to 30° C) for a maximum 4 hours.

DIRECTION FOR USE OF IV INFUSION: Pantoprazole IV infusion should be given as an intravenous infusion over a period of approximately 15 minutes. Pantoprazole IV infusion should be reconstituted with 10 ml of 0.9% Sodium Chloride Injection and further diluted (admixed) with 0.9% Sodium Chloride Injection or 5% Dextrose or Lactated Ringer's Injection to a final volume of 100 ml. The reconstituted solution may be stored at room temperature (up to 30° C) for a maximum 4 hours prior to further dilution. The admixed solution may be stored at room temperature (up to 30° C) and must be used within 24 hours from the time of initial reconstitution.

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.

No potentially life-threatening effects have been reported with Pantoprazole. Symptomatic adverse effects include headache and diarrhoea are two common reported adverse effects. Peripheral edema has been occasionally reported in female patients. Other side effects may include abdominal pain, dizziness, nausea, epigastric discomfort, flatulence, skin rash, pruritus etc.

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.

Rat Oral LD 50 747 mg/kg

Tumorigenicity

Because of the chronic nature of GERD, there may be a potential for long-term administration of pantoprazole. In long-term rodent studies, pantoprazole was carcinogenic and its administration lead to rare types of gastrointestinal tumors. The relevance of these findings to tumor development in humans is unknown at this time.

Teratogenic Effects

This drug falls under pregnancy category B category. Reproduction studies have been performed in rats at oral doses up to 88 times the recommended human dose (RHD), as well as in rabbits at oral doses up to 16 times the RHD, and have shown no evidence of impaired fertility or harm to the fetus caused by pantoprazole. No adequate and well-controlled studies in pregnant women have been completed. Because animal reproduction studies are not always predictive of human response, this drug should only be used during pregnancy if clearly required.

Nursing Mothers

Pantoprazole and its metabolites have been found to be excreted in the milk of rats. Pantoprazole excretion in human milk has been found in a study performed with a single nursing mother after one 40 mg oral dose. The clinical relevance of this finding is not known, however, it is advisable to take note of this finding when considering pantoprazole use during nursing. Many drugs excreted in human breastmilk have a risk for serious adverse effects in nursing infants.

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 should be cautioned that Pantoprazole tablet should not be split, crushed or chewed. The tablet should be swallowed whole, with or without food in the stomach. Concomitant administration of antacid does not affect the absorption of Pantoprazole.

Interaction

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

There is no interaction with concomitantly administered antacids. No dosage adjustment is needed with combination use of the following drugs: Theophylline, Caffeine, Diazepam, Digoxin, Ethanol, Metoprolol, Nifedipine or Warfarin.

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 apparent volume of distribution of pantoprazole is approximately 11.0-23.6 L, distributing mainly in the extracellular fluid.

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.

Pantoprazole is absorbed after oral administration as an enteric-coated tablet with maximum plasma concentrations attained within 2 – 3 hours and a bioavailability of 77% that does not change with multiple dosing . Following an oral dose of 40mg, the Cmax is approximately 2.5 μg/mL with a tmax of 2 to 3 hours. The AUC is approximately 5 μg.h/mL. There is no food effect on AUC (bioavailability) and Cmax.

Delayed-release tablets are prepared as enteric-coated tablets so that absorption of pantoprazole begins only after the tablet leaves the stomach.

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.

About 1 hour

Clearance

Diclofenac has a plasma clearance 16 L/h.

Adults: With intravenous administration of pantoprazole to extensive metabolizers, total clearance is 7.6-14.0 L/h. In a population pharmacokinetic analysis, the total clearance increased with increasing body weight in a non-linear fashion.

Children: clearance values in the children 1 to 5 years old with endoscopically proven GERD had a median value of 2.4 L/h.

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.

After a single oral or intravenous (IV) dose of 14C-labeled pantoprazole to healthy, normal metabolizing subjects, about 71% of the dose was excreted in the urine, with 18% excreted in the feces by biliary excretion. There was no kidney excretion of unchanged pantoprazole.

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.

There are no adequate or well-controlled studies in pregnant women. Pantoprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether Pantoprazole is excreted in human breast milk. Pantoprazole should be used during lactation only if the potential benefit justifies the potential risk.

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

It is contraindicated in patients with known hypersensitivity to Pantoprazole.

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.

There are no known symptoms of overdosage in humans. Since Pantoprazole is highly protein bound, it is not readily dialyzable. Apart from symptomatic and supportive management, no specific therapy is recommended.

Storage Condition

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

Store in a cool, dry place and away from light. Keep out of the reach of children.

Innovators Monograph

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