CETACHLOR (IHS)
Uncoated Tablet
Paracetamol 500 Mg IP
Chlorzoxazone 250 Mg IP
CETACHLOR contains paracetamol and chlorzoxazone in combination. Paracetamol is a para-aminophenol derivative that exhibits analgesic and anti-pyretic activity. Its mechanism of action is believed to include inhibition of prostaglandin synthesis, primarily within the central nervous system. It does not possess anti-inflammatory activity. It provides relief from mild to moderate pain and fever. Chlorzoxazone is a centrally acting muscle relaxant and used in painful musculoskeletal disorders. This medication helps in relieving muscle pain. Chlorzoxazone is a muscle relaxant which works by acting on the central nervous system. Paracetamol works by lowering the chemical substance (prostaglandins) in the body that causes pain.
CLINICAL PARTICULARS
Therapeutic Indications
Paracetamol:
For the treatment of mild to moderate pain including headache, migraine, neuralgia, toothache, sore throat, period pains, aches and pains, symptomatic relief of rheumatic aches and pains and of influenza, feverishness and feverish colds.
Chlorzoxazone:
For the relief of discomfort associated with acute painful musculoskeletal conditions. Moderate to Severe Muscle Spasm
Posology and Method of Administration
Paracetamol:
Adults, The Elderly and Young Person’s 16 Years and over: 2 tablets every 4 hours to a maximum of 8 tablets in 24 hours.
Children 6 – 9 Years: ½ tablet every 4 hours to a maximum of 4 doses in 24 hours.
Children 10 – 11 Years: 1 tablet every 4 hours to a maximum of 4 doses in 24 hours
Adolescents 12 – 15 Years: 1 to 1 ½ tablets every 4 hours to a maximum of 4 doses in 24 hours
Do not give to children aged under 6 years of age.
Chlorzoxazone:
Usual Adult Dosage
One tablet three or four times daily. If adequate response is not obtained with this dose, it may be increased to (750 mg) three or four times daily. As improvement occurs dosage can usually be reduced.
CONTRAINDICATIONS
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Paracetamol:
Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor.
Chlorzoxazone:
Serious (including fatal) hepatocellular toxicity has been reported rarely in patients receiving chlorzoxazone. The mechanism is unknown but appears to be idiosyncratic and unpredictable. Factors predisposing patients to this rare event are not known. Patients should be instructed to report early signs and/or symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, or jaundice. Chlorzoxazone should be discontinued immediately and a physician consulted if any of these signs or symptoms develop. Chlorzoxazone use should also be discontinued if a patient develops abnormal liver enzymes (e.g., AST, ALT, alkaline phosphatase and bilirubin.)
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION
FERTILITY, PREGNANCY AND LACTATION
Paracetamol:
A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency. Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding.
Chlorzoxazone:
The safe use of chlorzoxazone has not been established with respect to the possible adverse effects upon fetal development. Therefore, it should be used in women of childbearing potential only when, in the judgment of the physician, the potential benefits outweigh the possible risks.
Effects on Ability to Drive and Use Machines
None known.
UNDESIRABLE EFFECTS
Paracetamol:
Adverse effects of paracetamol are rare. Very rare cases of serious skin reactions have been reported. There have been reports of blood dyscrasias including thrombocytopenia purpura, methaemoglobenaemia and agranulocytosis, but these were not necessarily causality related to paracetamol.
Chlorzoxazone:
It is possible in rare instances that chlorzoxazone may have been associated with gastrointestinal bleeding. Drowsiness, dizziness, lightheadedness, malaise, or over-stimulation may be noted by an occasional patient. Rarely, allergic type skin rashes, petechiae, or ecchymoses may develop during treatment. Angioneurotic edema or anaphylactic reactions are extremely rare. There is no evidence that the drug will cause renal damage. Rarely, a patient may note discoloration of the urine resulting from a phenolic metabolite of chlorzoxazone. This finding is of no known clinical significance.
Overdose
Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors.
Risk Factors
If the patient
a) Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.
Or
b) Regularly consumes ethanol in excess of recommended amounts.
Or
c) Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.
Symptoms
Symptoms of paracetamol over dosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, hemorrhage, hypoglycemia, cerebral edema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, hematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.
Management
Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamics’ Properties
Paracetamol is a para-aminophenol derivative that exhibits analgesic and anti-pyretic activity. Its mechanism of action is believed to include inhibition of prostaglandin synthesis, primarily within the central nervous system. It does not possess anti-inflammatory activity. It provides relief from mild to moderate pain and fever.
Chlorzoxazone is a centrally-acting agent for painful musculoskeletal conditions. Data available from animal experiments as well as human study indicate that chlorzoxazone acts primarily at the level of the spinal cord and subcortical areas of the brain where it inhibits multisynaptic reflex a.c. involved in producing and maintaining skeletal muscle spasm of varied etiology. The clinical result is a reduction of the skeletal muscle spasm with relief of pain and increased mobility of the involved muscles.
Mechanisms of Action
Analgesic – the mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, through a peripheral action by blocking pain-impulse generation.
The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation. Antipyretic – paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat-regulation center to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus. Chlorzoxazone inhibits degranulation of mast cells, subsequently preventing the release of histamine and slow-reacting substance of anaphylaxis (SRS-A), mediators of type I allergic reactions. Chlorzoxazone also may reduce the release of inflammatory leukotriene. Chlorzoxazone may act by inhibiting calcium and potassium influx which would lead to neuronal inhibition and muscle relaxation. Data available from animal experiments as well as human study indicate that chlorzoxazone acts primarily at the level of the spinal cord and subcortical areas of the brain where it inhibits multisynaptic reflex arcs involved in producing and maintaining skeletal muscle spasm
Pharmacokinetic Properties
Absorption
Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion.
It is metabolized in the liver and excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations. A minor hydroxylated metabolite which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol over dosage and cause liver damage.
Distribution
Paracetamol is distributed into most body tissues. Binding to the plasma proteins is minimal at therapeutic concentrations but increases with increasing doses.
Metabolism
Paracetamol is metabolized extensively in the liver and excreted in the urine mainly as inactive glucuronide and sulphate conjugates. The metabolites of paracetamol include a minor hydroxylated intermediate which has hepatotoxic activity. This intermediate metabolite is detoxified by conjugation with glutathione. However, it can accumulate following paracetamol over dosage (more than 150 mg/kg or 10 g total paracetamol ingested) and, if left untreated, can cause irreversible liver damage. Paracetamol is metabolized differently by premature infants, newborns, infants and young children compared to adults, the sulfate conjugate being predominant. Chlorzoxazone is rapidly metabolized and is excreted in the urine, primarily in a conjugated form as the glucuronide.
Excretion
Paracetamol is excreted in the urine mainly asthe glucuronide and sulfate conjugates.
Less than 5% is excreted unchanged. Approximately 85% of a dose of paracetamol is excreted in urine as free and conjugated paracetamol within 24 hours of ingestion. Administration of paracetamol to patients with moderate to severe renal impairment may result in accumulation of paracetamol conjugates. The elimination half-life varies from one to three hours.
Special Precautions for Storage
Do not store above 25°C.