Thiofen

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.

Thiocolchicoside is a semi-synthetic colchicine derivative used as an analgesic and anti-inflammatory.

Thiocolchicoside is a skeletal muscle-relaxant drug used in the treatment of orthopedic, traumatic and rheumatologic disorders . It is indicated as an adjuvant drug in the treatment of painful muscle contractures and is indicated in acute spinal pathology, for adults and adolescents 16 years of age and older . Recent studies have examined its effect on muscle tone, stiffness, contractures, and soreness experienced by athletes during sporting competitions .

Thiofen 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 miosisBack Pain, Acute, Chronic Back Pain, Extra-Articular Rheumatism, Muscle Inflammation, Muscle Spasms, Musculoskeletal Pain, Nonspecific Pain Post Traumatic Injury, Osteoarthritis (OA), Pain, Post Surgical Pain, Post-traumatic pain, Postoperative pain, Rheumatoid Arthritis, Soreness, Muscle, Spasms, Spinal pain, Vertebral column pain, Inflammation localized, Localized pain, Mild to moderate pain, Musculoskeletal spasms

How Thiofen 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.

Thiocolchicoside, is a synthetic sulfur derivative of colchicoside, a naturally occurring glucoside contained in the Colchicum autumnale plant. Thiocolchicoside has a selective and potent affinity for g-aminobutyric acid A (GABA-A) receptors and acts on muscular contractures by activating the GABA inhibitory pathways thereby behaving as a potent muscle relaxant . Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex . GABAergic neurons are involved in myorelaxation, anxiolytic treatment, sedation, and anesthetics. GABA can also modulate heart rate and blood pressure.

It also has an affinity for the inhibitory glycine receptors (i.e., have glycomimetic and GABA mimetic activity), therefore acts as a muscle relaxant. Glycine is an inhibitory neurotransmitter and acts as an allosteric regulator of NMDA (N-methyl-D-aspartate) receptors. It is involved in the processing of motor and sensory data, thereby regulating movement, vision, and audition. Inhibitory neurotransmitter in spinal cord, allosteric regulator of NMDA receptors .

In one study, thiocolchicoside inhibited the function of recombinant human strychnine-sensitive glycine receptors composed of the alpha1 subunit with a potency (median inhibitory concentration of 47 microM) lower than that apparent with recombinant GABA(A) receptors. The drug also inhibited the function of human nicotinic acetylcholine receptors made of the alpha4 and beta2 subunits, however, this effect was partial and moreover only apparent at high concentrations. Thiocolchicoside demonstrated no effect on the function of 5-HT(3A) serotonin receptors .

Dosage

Thiofen 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.

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.

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.

Has been shown to cause chromosomal aneuploidy and male infertility. Should be avoided during all stages of pregnancy, lactation and puberty. Is a potential risk factor for cancer.

In 2013, The European Medical Association (EMA) mandated that the use of thiocolchicoside-containing medicines by mouth or injection should be restricted across the European Union (EU). These drugs are now recommended only as an add-on treatment for painful muscle contractures resulting from spinal conditions in adults and adolescents 16 years old and older. Additionally, the dose of thiocolchicoside by mouth or injection should be limited. This is due to experimental evidence suggesting that thiocolchicoside was metabolized into M2 or SL59.0955, that has the propensity to damage dividing cells, resulting in aneuploidy (an abnormal number or arrangement of chromosomes). As a result, the CHMP (committee for medicinal products for human use) examined the safety profile of this medicine and consider what regulatory action might be appropriate .

The CHMP reviewed the evidence, with consideration of opinions from experts in medicines safety, and concluded that aneuploidy may occur with M2 at levels not significantly greater than those measured after recommended doses of thiocolchicoside ingested orally. Aneuploidy is a strong risk factor for fetal harm, decreased fertility in men, and could theoretically increase the risk of developing cancer .

The maximum recommended oral dose is 8 mg every 12 hours; treatment length should not exceed 7 consecutive days. When given intramuscularly (IM), the maximum dose is 4 mg every 12 hours, for a maximum of 5 days .

In addition to the above toxicity, a study was done on the hepatotoxic potential of thiocolchicoside. It was observed that serum AST and ALT levels increased following of the administration oral thiocolchicoside at 8 mg/day. Two weeks after discontinuing thiocolchicoside therapy, liver enzymes had decreased to levels within the normal range. Although infrequent, thiocolchicoside should be considered a rare hepatotoxic agent in clinical practice .

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.

Interaction

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

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 thiocolchicoside is estimated to be approximately 42.7 L after an intramuscular injection of 8 mg .

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.

Oral bioavailability is ~25% After intramuscular administration, thiocolchicoside Cmax occur in 30 min and .reach values of 113 ng/mL after a 4 mg dose and 175 ng/mL after a 8 mg dose. The corresponding values of AUC are respectively 283 and 417 ng.h/mL. The pharmacologically active metabolite SL18.0740 is found at lower concentrations with a Cmax of 11.7 ng/mL occurring 5 h post administration and an AUC of 83 ng.h/mL .

After oral administration, no thiocolchicoside is detected in plasma. Only two metabolites are observed: The pharmacologically active metabolite SL18.0740 and an inactive metabolite SL59.0955. For both metabolites, maximum plasma concentrations occur 1hour after thiocolchicoside administration. After a single oral dose of 8 mg of thiocolchicoside the Cmax and AUC of SL18.0740 are about 60 ng/mL and 130 ng.h/mL respectively. For SL59.0955 these values are much lower: Cmax around 13 ng/mL and AUC ranging from 15.5 ng.h/mL (until 3h) to 39.7 ng.h/mL (until 24h) .

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.

Approximately 7.7h .

Clearance

Diclofenac has a plasma clearance 16 L/h.

Primarily extrarenal elimination (75% of the total body clearance) .

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.

Thiocolchicoside is not eliminated unchanged, rather as one of three metabolites found in either feces (~79 %) or in urine 20%. 3- demethylcolchicine (M2) and 3-O-glucurono-demethylcolchicine (M1) are found in both urine and feces, where as di-demethylcolchicine is found only in feces .

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.

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

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.

Innovators Monograph

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