Revodol Spas

Uses

Dicycloverine is used for:

• Functional bowel/ irritable bowel syndrome
• Urinary incontinence secondary to unstable detrusor muscle
• Infantile colic
• GIT spasm
• Colicky abdominal pain
• Diverticulitis
• Abdominal colic

Paracetamol IV is used for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, the reduction of fever.

Paracetamol is a non-salicylate antipyretic and non-opioid analgesic agent. Paracetamol IV injection is a sterile, clear, colorless, non pyrogenic, isotonic formulation of Paracetamol intended for intravenous infusion.

Tramadol is used for the treatment of moderate to severe painful conditions. These include: Postoperative pain, Colic and spastic pain, Cancer pain, Joint pain, Neck and back pain & Pain associated with osteoporosis.

Revodol Spas is also used to associated treatment for these conditions: Functional bowel syndrome, Irritable Bowel Syndrome (IBS), Gastrointestinal cramps caused by GasAcute Gouty Arthritis, Acute Musculoskeletal Pain, Allergies, Ankylosing Spondylitis (AS), Arthritis, Chills, Cold, Cold Symptoms, Common Cold, Common Cold/Flu, Cough, Cough caused by Common Cold, Coughing caused by Flu caused by Influenza, Dyskinesia of the Biliary Tract, Dyskinesia of the Urinary Tract, Febrile Convulsions, Febrile Illness Acute, Fever, Fibromyalgia Syndrome, Flu caused by Influenza, Headache, Joint dislocations, Menstrual Distress (Dysmenorrhea), Mild pain, Muscle Inflammation, Muscle Injuries, Muscle Spasms, Musculoskeletal Pain, Nasal Congestion, Neuralgia, Osteoarthritis (OA), Pain, Pollen Allergy, Postoperative pain, Premenstrual cramps, Rheumatoid Arthritis, Rhinopharyngitis, Rhinorrhoea, Severe Pain, Sinusitis, Soreness, Muscle, Spasms, Spastic Pain of the Gastrointestinal Tract, Sprains, Tension Headache, Toothache, Upper Respiratory Tract Infection, Whiplash Syndrome, Acute Torticollis, Mild to moderate pain, Minor aches and pains, Minor pain, Moderate Pain, Airway secretion clearance therapy, Antispasmodic, BronchodilationPain, Acute, Premature Ejaculation, Severe Pain, Acute, moderate, severe Pain, Moderate Pain

How Revodol Spas works

Dicyclomine achieves its action partially through direct antimuscarinic activity of the M1, M3, and M2 receptors; and partially through antagonism of bradykinin and histamine. Dicyclomine non-competitively inhibits the action of bradykinin and histamine, resulting in direct action on the smooth muscle, and decreased strength of contractions seen in spasms of the ileum.

Tramadol is a centrally acting μ-opioid receptor agonist and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine. Tramadol binds weakly to κ- and δ-opioid receptors and to the μ-opioid receptor with 6000-fold less affinity than morphine.

Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain.

In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding.

Tramadol has also been shown to affect a number of pain modulators including alpha2-adrenoreceptors, neurokinin 1 receptors, the voltage-gated sodium channel type II alpha subunit, transient receptor potential cation channel subfamily V member 1 (TRPV1 - also known as the capsaicin receptor), muscarinic receptors (M1 and M3), N-methyl-D-aspartate receptor (also known as the NMDA receptor or glutamate receptor), Adenosine A1 receptors, and nicotinic acetylcholine receptor.

In addition to the above neuronal targets, tramadol has a number of effects on inflammatory and immune mediators involved in the pain response. This includes inhibitory effects on cytokines, prostaglandin E2 (PGE2), nuclear factor-κB, and glial cells as well as a change in the polarization state of M1 macrophages.

Dosage

Revodol Spas dosage

Oral dosage forms-

• Adults:10 to 20 mg three times a day.
• Children >6 months of age: 5 to 10 mg three times a day.
• Children <6 months of age: Dose must be determined by the doctor.

Oral dicycloverine Hydrochloride should be started as soon as possible

Intramuscular dosage form

• Adults:Intramuscular injection. Not for intravenous use. The recommended intramuscular dose is 80 mg daily (in 4 equally divided doses).

Intramuscular dosage form should not be used for periods longer than 1 or 2 days.

Adults and adolescents weighing 50 kg and over: the recommended dosage of Paracetamol IV is 1000 mg every 6 hours or 650 mg every 4 hours, with a maximum single dose of Paracetamol IV of 1000 mg, a minimum dosing interval of 4 hours, and a maximum daily dose of Paracetamol of 4000 mg per day.

Adults and adolescents weighing under 50 kg: the recommended dosage of Paracetamol IV is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximum single dose of Paracetamol IV of 15 mg/kg, a minimum dosing interval of 4 hours, and a maximum daily dose of Paracetamol of 75 mg/kg per day.

Children >2 to 12 years of age: the recommended dosage of Paracetamol IV is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximum single dose of Paracetamol IV of 15 mg/kg, a minimum dosing interval of 4 hours, and a maximum daily dose of Paracetamol of 75 mg/kg per day.

Capsule or Tablet: Usual doses are 50 to 100 mg every four to six hours. For acute pain an initial dose of 100 mg is required. For chronic painful conditions an initial dose of 50 mg is recommended. Subsequent doses should be 50 to 100 mg administered 4-6 hourly. The dose level and frequency of dosing will depend on the severity of the pain.The total daily dosage by mouth should not exceed 400 mg.

Sustained Release Capsuleor Tablet: One SR capsuleor tablet every 12 hours, for example first one in the morning and then at the same time in the evening. The number of capsules taken at a time will depend upon severity of pain, but it should not be taken more frequently than every 12 hours.The total daily dosage by mouth should not exceed 400 mg.

Injection: A dose of 50-100 mg may be given every 4 to 6 hours by intramuscular or by intravenous infusion. For the treatment of postoperative pain,the initial dose is 100 mg followed by 50 mg every 10 to 20 minutes if necessary to a maximum of 250 mg in the first hour. Thereafter, doses are 50 to 100 mg every 4 to 6 hours up to a total daily dose of 600 mg.

Suppository: Tramadol suppository should be administered rectally. For adults usual dose is 100 mg Tramadol Hydrochloride 6 hourly. In general, 400 mg Tramadol Hydrochloride (4 Tramadol suppository) per day sufficient. However, for the treatment of Cancer pain and severe pain after operations much higher daily doses can be used.

Side Effects

Insomnia, mydriasis, cycloplegia, increased ocular tension, urinary hesitancy, palpitations, dyspnea.

As all paracetamol products, adverse drug reactions are rare (>1/10000, <1/1000) or very rare (<1/10000). Frequent adverse reactions at injection site have been reported during clinical trials (pain and burning sensation). Very rare cases of hypersensitivity reactions ranging from simple skin rash or urticaria to anaphylactic shock have been reported and require discontinuation of treatment. Cases of erythema, flushing, pruritus and tachycardia have been reported.

Commonly occurring side-effects are dizziness/vertigo, nausea, constipation, headache, somnolence, vomiting, pruritus, CNS stimulation, asthenia, sweating, dyspepsia, dry mouth, diarrhoea.

Less commonly occurring side-effects include malaise, allergic reaction, weight loss, vasodilatation, palpitations, abdominal pain, anorexia, flatulence, GI bleeding, hepatitis, stomatitis etc.

Toxicity

Patients experiencing an overdose may present with headache, nausea, vomiting, blurred vision, dilated pupils, dizziness, dry mouth, difficulty swallowing, CNS stimulation, as well as hot, dry skin. Treat patients with gastric lavage, emetics, activated charcoal, sedatives for excitement, and a cholinergic agent if indicated.

The oral LD₅₀ in mice is 625mg/kg.

The reported LD50 for tramadol, when administered orally in mice, is 350 mg/kg.

In carcinogenic studies, there are reports of murine tumors which cannot be concluded to be carcinogenic in humans. On the other hand, tramadol showed no evidence to be mutagenic in different assays and does not have effects on fertility. However, there are clear reports of embryotoxicity and fetotoxicity.

Precaution

Use with caution in patients with autonomic neuropathy, hepatic or renal disease, ulcerative colitis, coronary heart disease, congestive heart failure, cardiac tachyarrhythmia, known or suspected prostatic hypertrophy.

Administration of Paracetamol in doses higher than recommended may result in hepatic injury, including the risk of severe hepatotoxicity and death. Do not exceed the maximum recommended daily dose of Paracetamol. Use caution when administering Paracetamol in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance < 30 ml/min). There were infrequent reports of life-threatening anaphylaxis requiring emergent medical attention. Discontinue Paracetamol IV immediately if symptoms associated with allergy or hypersensitivity occurs. Do not use Paracetamol IV in patients with Paracetamol allergy.

Respiratory depression: When large doses of tramadol are administered with anaesthetic with anaesthetic medications or alcohol, respiratory depression may result. Therefore, tramadol should be administered cautiously in patients at risk for respiratory depression.

Opioid dependence: Tramadol is not recommended for patients who are dependent on opioids.

Concomitant CNS depressants: Tramadol should be used with caution and in reduced dosages when administering to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, phenothiazines, tranquilizers or sedative hypnotics.

Concomitant MAO inhibitors: Tramadol should be used with great caution in patients taking MAO inhibitors, since tramadol inhibits the uptake of norepinephrine and serotonin.

Tramadol should be used with caution in patients with increased intracranial pressure or head injury and patients with acute abdominal conditions.

Interaction

The following agents may increase certain actions or side-effects of Dicycloverine-antiarrhythmic agents, antihistamines, antipsychotic agents, benzodiazepines, MAO inhibitors, narcotic analgesics, nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants and other drugs having anticholinergic activity.

In general, physician need not be concerned about drugs interacting with Tramadol. The monoamine oxidase (MAO) inhibitors represent the only drug class not recommended for combination with Tramadol. Concomitant administration of carbamazepine with Tramadol causes a significant increase in Tramadol metabolism and it requires to increase the dose of Tramadol.

Volume of Distribution

The volume of distribution for a 20mg oral dose is 3.65L/kg.

Volume of distribution is about 0.9L/kg. 10 to 20% of the drug is bound to red blood cells. Acetaminophen appears to be widely distributed throughout most body tissues except in fat.

The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg. Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration. Tramadol crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration. It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations.

Elimination Route

The bioavailability of dicyclomine has not been determined, though it is likely well absorbed as the primary route of elimination is in the urine. Dicyclomine has a T_max of 1-1.5h.

Oral Administration

Tramadol is administered as a racemate, with both the [-] and [+] forms of both tramadol and the M1 metabolite detected in circulation. Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%. This difference in absorption and bioavailability can be attributed to the 20-30% first-pass metabolism. Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively. Following a single oral dose of 100mg of tramadol, the Cmax was found to be approximately 300μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55μg/L with a Tmax of 3 hours.

Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing. There is no evidence of self-induction. Following multiple oral doses, Cmax is 16% higher and AUC is 36% higher than after a single dose, demonstrating a potential role of saturable first-pass hepatic metabolism in increasing bioavailability.

Intramuscular Administration

Tramadol is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of tramadol, Cmax of 166μg/L was found with a Tmax of 0.75 hours.

Rectal Administration

Following rectal administration with suppositories containing 100mg of tramadol, Cmax of 294μg/L was found with a Tmax of 3.3 hours. The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to oral administration.

Half Life

The mean plasma elimination half life is approximately 1.8 hours.

The half-life for adults is 2.5 h after an intravenous dose of 15 mg/kg. After an overdose, the half-life can range from 4 to 8 hours depending on the severity of injury to the liver, as it heavily metabolizes acetaminophen.

Tramadol reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 hours.

Clearance

Data regarding the clearance of dicyclomine is not readily available.

Adults: 0.27 L/h/kg following a 15 mg/kg intravenous (IV) dose. Children: 0.34 L/h/kg following a 15 mg/kg intravenous (IV dose).

In clinical trials, the clearance rate of tramadol ranged from 3.73 ml/min/kg in renal impairment patients to 8.50 ml/min/kg in healthy adults.

Elimination Route

Dicyclomine is 79.5% eliminated in the urine and 8.4% in the feces.

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.

The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.

Pregnancy & Breastfeeding use

Pregnancy: Category B. Dicycloverine was neither teratogenic nor embryocidal in animal trial. It, like other drugs should be used during pregnancy only if clearly needed. There are no data on the secretion of this drug into breast milk. Dicycloverine should be used cautiously in case of lactating mother.

Pregnancy Category C. There are no studies of intravenous Paracetamol in pregnant women; however, epidemiological data on oral Paracetamol use in pregnant women show no increased risk of major congenital malformations. Animal reproduction studies have not been conducted with IV Paracetamol and it is not known whether Paracetamol IV can cause fetal harm when administered to a pregnant woman. Paracetamol IV should be given to a pregnant woman only if clearly needed. There are no adequate and well-controlled studies with Paracetamol IV during labor and delivery; therefore, it should be used in such settings only after a careful benefit-risk assessment. While studies with Paracetamol IV have not been conducted, Paracetamol is secreted in human milk in small quantities after oral administration.

Safe use of Tramadol in pregnancy has not been established. Tramadol has been shown to cross the placenta. There are no adequate and well-controlled studies in pregnant women. Therefore, Tramadol should be used during pregnancy only if the potential benefit justifies the risk to the foetus. Tramadol Hydrochloride should not be administered during breast feeding as Tramadol and its metabolites have been detected in breast milk.

Contraindication

Dicycloverine is contraindicated in:

• Obstructive uropathy
• Obstructive disease of the gastrointestinal tract
• Severe ulcerative colitis
• Reflux esophagitis
• Unstable cardiovascular status in acute hemorrhage
• Glaucoma
• Myasthenia gravis
• Evidence of prior hypersensitivity to dicycloverine hydrochloride or other ingredients of this formulation
• Infants less than 6 months of age

Paracetamol is contraindicated in patients with known hypersensitivity to its active ingredient or to any of the excipients in the intravenous formulation. Also contraindicated in patients with severe hepatic impairment or severe active liver disease

Tramadol is contraindicated in persons having hypersensitivity to this drug. It is also contraindicated in acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs.

Special Warning

Pediatric Use: The safety and effectiveness of Paracetamol IV for the treatment of acute pain and fever in pediatric patients ages 2 years and older is supported by evidence from adequate and well-controlled studies of Paracetamol IV in adults.

Geriatric use: No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Patients with Hepatic Impairment: Paracetamol is contraindicated in patients with severe hepatic impairment or severe active liver disease and should be used with caution in patients with hepatic impairment or active liver disease. A reduced total daily dose of Paracetamol may be warranted.

Patients with Renal Impairment: In cases of severe renal impairment (creatinine clearance < 30 ml/min), longer dosing intervals and a reduced total daily dose of Paracetamol may be warranted.

Paediatric use: The paediatric use of Tramadol is not recommended because safety and efficacy in patients under 16 years of age have not been established.

Use in children: Use in children from the age of 1 year Tramadol Hydrochloride can be given in a dose of 1-2 mg/kg body weight. However,suppository (100 mg Tramadol Hydrochloride) should not be administered in children and adolescents below the age of 14 years. Tramadol Hydrochloride 100 mg SR Capsules have not been studied in children. Therefore,safety and efficacy have not been established and the product should not be used in children.

Renal Impairment: Oral:

• CrCl <10: Contraindicated.
• CrCl 10 to <30: Increase dosing interval to 12. Max: 200 mg/day; Contraindicated (extended-release tab).

Parenteral:

• CrCl <10: Contraindicated.
• CrCl 10-30: Increase dosing interval to 12 hrly.

Hepatic Impairment:

• Oral: Severe: Increase dosing interval to 12 hrly; Contraindicated (extended-release).
• Parenteral: Severe: Increase dosing interval to 12 hrly.

Acute Overdose

Toxic reaction seldom occurs with dicycloverine. The signs and symptoms of overdosage are headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation.

Storage Condition

Store below 30°C.

Store in a cool & dry place & away from children. For single use only. The product should be used within 6 hours after opening. Do not refrigerate or freeze.

Store below 30° C, protected from light and moisture. Keep all medicines out of reach of children.

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