Stelbid Spas

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.

Spastic conditions of the gastrointestinal tract, irritable bowel syndrome-

• Biliary colics and spastic conditions of the biliary tract: Cholecystolithiasis, cholecystitis, cholangitis.
• Renal colics and spastic conditions of the urogenital tract: Nephrolithiasis, ureterolithiasis, pyelitis, cystitis.
• Spastic conditions of the uterus: Dysmenorrhea, imminent abortion, uterine tetanus.

Stelbid Spas 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 miosisAbdominal Pain caused by Gall Stones, Abdominal Pain caused by Kidney Stones, Muscle Spasms, Spastic Pain, Spastic Pain caused by Cystitis, Spastic Pain caused by Funicular Nephritis, Spastic Pain caused by Gallbladder disorders, Spastic Pain caused by Physical Examination, Spastic Pain caused by cholecysitis, Spastic Pain of the Gastrointestinal Tract

How Stelbid Spas 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.

Drotaverine is a selective inhibitor of phosphodiesterase 4 (PDE4), which is an enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP). Inhibition of PDE4 leads to elevated levels of cAMP, leading to smooth muscle relaxation. Recent research showed that low levels of cAMP have been associated with brain tumorigenesis, leading to the investigation of PDE4 inhibitors as potential anticancer agents.

Dosage

Stelbid Spas 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.

Oral-

• Adults: 1 to 2 tablets, 3 times daily
• Children (over 6 years): 1/2 to 1 tablet, 1-2 times daily.
• Children (1-6 years): 1/4 to 1/2 tablet, 1-2 times daily.

Injection-

• Adults: 1 to 2 ampoules, intramuscularly or subcutaneously, 1-3 times daily.
• For the management of acute stone colics: 1 or 2 ampoules by slow intravenous injection.

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.

The common side effects are headache, dizziness, rhinitis, sinusitis, gastrointestinal upset, nausea, pharyngitis, edema 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.

Oral LD₅₀ is 540 mg/kg in rats and 350 mg/kg in mice. There is limited information on drotaverine overdose and toxicity.

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.

Caution should be taken for patients suffering from liver and kidney disease.

Interaction

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

May attenuate the action of levodopa. Concurrent use of analgesics, antimuscarinics or benzodiazepines. Additive beneficial effect with concurrent use of analgesics, antimuscarinics or benzodiazepines.

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.

Following oral administration of a single 80 mg dose, the mean volume of distribution was 193 ± 48 L. Following an intravenous dose of 80 mg, the mean volume of distribution was 195 ± 48 L.

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.

Drotaverine is not completely absorbed following oral administration and its bioavailability is highly variable. Following oral administration of a single 80 mg dose, the absolute bioavailability ranged between 24.5 and 91 % with a mean of 58.2 ± 18.2%. Mean C_max was 292 ± 88 ng/mL. Mean AUC was 3251 ± 950 ng*h/mL. Mean T_max was 1.9 ± 0.54 hours.

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 oral administration of a single 80 mg dose, the mean half-life was 9.11 ± 1.29 hours. Following an intravenous dose of 80 mg, the mean half-life 9.33 ± 1.02 hours.

Clearance

Diclofenac has a plasma clearance 16 L/h.

Following oral administration of a single 80 mg dose, the mean renal clearance was 0.59 ± 0.18 mL/min. Following an intravenous dose of 80 mg, the mean renal clearance was 0.73 ± 0.29 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.

Drotaverine is mainly eliminated via hepatic metabolism. About 67% of the drug is found in feces and 20% of the drug was eliminated with urine.

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.

As with most drugs, the use of Drotaverine Hydrochloride should be avoided during pregnancy and lactation unless essential.

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

Drotaverine is contraindicated in patients with known hypersensitivity to the products and its constituents.

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.

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