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PARAFON FORTE® C8
Johnson & Johnson • Merck
Chlorzoxazone - Acetaminophen - Codeine Phosphate
Analgesic - Muscle Relaxant
 
Action And Clinical Pharmacology: Parafon Forte C8 combines the muscle-relaxant effect of chlorzoxazone with acetaminophen, a well-known analgesic, and codeine, a centrally-acting narcotic analgesic.

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 arcs 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. Blood levels of chlorzoxazone can be detected in humans during the first 30 minutes after oral administration of Parafon Forte C8 and peak levels may be reached in about 1 to 2 hours. Chlorzoxazone is rapidly metabolized and is excreted in the urine, primarily in a conjugated form as the glucuronide. Less than 1% of a dose of chlorzoxazone is excreted unchanged in the urine in 24 hours.

Acetaminophen provides analgesic action to supplement that which results secondarily from muscle relaxation. Acetaminophen is rapidly absorbed after oral administration, with peak plasma levels occurring in 1 to 2 hours. After 8 hours, only negligible amounts remain in the blood. Only 4% is excreted unchanged; 85% of the ingested dose is recovered in the urine in conjugated form as the glucuronide. Acetaminophen is distributed throughout most tissues of the body. Acetaminophen is metabolized primarily in the liver. Little unchanged drug is excreted in the urine, but most metabolic products appear in the urine within 24 hours.

Codeine supplements the analgesic action of acetaminophen and it retains at least one-half of its analgesic activity when administered orally. A reduced first-pass metabolism of codeine by the liver accounts for the greater oral potency of codeine when compared to most other morphine-like narcotics. Following absorption, codeine is metabolized by the liver and metabolic products are excreted in the urine. Approximately 10% of the administered codeine is demethylated to morphine, which may account for its analgesic activity.

The combination of acetaminophen and codeine provides a pain relieving action to supplement the relief which results secondarily from muscle relaxation. The mode of action of chlorzoxazone has not been clearly identified, but may be related to its sedative properties. Chlorzoxazone does not directly relax tense skeletal muscles in man.

Following oral administration of chlorzoxazone and acetaminophen in combination with codeine, all drugs are rapidly absorbed. Mean drug plasma concentrations reach a peak level in the majority of subjects in 45 to 90 minutes.

The plasma elimination half-life is about 1 hour for chlorzoxazone, ranges from 1.5 to 3.5 hours for acetaminophen and from 1.5 to 4 hours for codeine.

Metabolism is rapid; the principal metabolites are conjugates of glucuronic acid which are excreted primarily in the urine. Less than 1% of an administered dose of chlorzoxazone or codeine, and less than 4% of an administered dose of acetaminophen is excreted unchanged in the urine in 24 hours. Only traces of unchanged drug are excreted through the bile into the feces.

Indications And Clinical Uses: As an adjunct to rest, physical therapy and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. Such conditions may include skeletal muscle spasm and pain associated with sprains, strains and other traumatic muscle injuries; myalgias; arthritides; low back pain; tension headache; torticollis, fibrositis; spondylitis; and cervical root and disc syndromes.

Contra-Indications: Hypersensitivity to acetaminophen, chlorzoxazone or codeine, hepatic impairment and acute porphyria.

Precautions: Use with caution in patients with known allergies or with a history of allergic reactions to drugs. If a sensitivity reaction occurs such as urticaria, redness, or itching of the skin, the drug should be stopped.

There have been reports of liver damage associated with the use of chlorzoxazone-containing products. If any signs or symptoms suggestive of liver dysfunction are observed, the drug should be stopped.

Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.

Acute Abdominal Conditions: The administration of these drugs or other narcotics may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Special Risk Patients: These drugs should be given with caution to certain patients such as the elderly or debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease, and prostatic hypertrophy or urethral stricture.

Occupational Hazards: Drowsiness and dizziness can occur with the use of Parafon Forte C8. Codeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks. Patients using this drug should be cautioned about driving a car or operating potentially hazardous machinery if they become drowsy, dizzy or show impaired mental or physical abilities while taking this medication.

The patient should understand the single-dose and 24-hour dose limits, and the time interval between doses. Like other narcotic-containing medications, this drug is subject to the Narcotic Control Act.

Drug Interactions: Patients receiving other narcotic analgesics, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with this drug may exhibit an additive CNS depression. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Avoid consumption of alcohol while using this product.

The concurrent use of anticholinergics with codeine may produce paralytic ileus.

Pregnancy: Teratogenic Effects: Codeine. A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120 mg/kg level, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In another study a single 100 mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring.

There are no studies in humans, and the significance of these findings to humans, if any, is not known.

Parafon Forte C8 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Dependence and withdrawal signs have been reported in newborns whose mothers took opiates regularly during pregnancy. These signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. Signs usually appear during the first few days of life.

Labor and Delivery: Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see Overdose). The effects of codeine, if any, on the later growth, development, and functional maturation of the child is unknown.

Lactation: Chlorzoxazone and acetaminophen with codeine are not recommended during lactation because safety in nursing mothers has not been established. It is not known if chlorzoxazone is excreted in breast milk. Acetaminophen passes into breast milk but is not likely to have an adverse effect on the infant at therapeutic doses. Some studies, but not others, have reported detectable amounts of codeine in breast milk. The levels are probably not clinically significant after usual therapeutic dosage. The possibility of clinically important amounts being excreted in breast milk in individuals abusing codeine should be considered.

Children: These products contain codeine and should not be administered to children except on the advice of a physician. Because safety and effectiveness of Parafon Forte C8 have not been established in children such use is not recommended.

Drug Abuse and Dependence: Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of Parafon Forte C8. This drug should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic-containing medications.

Adverse Reactions: Regular use of acetaminophen has been shown to produce a slight increase in prothrombin time in patients receiving oral anticoagulants, but the clinical significance of this effect is not clear. As with other nonprescription analgesic drugs, physicians should supervise the use of acetaminophen in patients with alcoholism, serious kidney or serious liver disease. Patients are advised to consult a physician if symptoms do not improve or if new problems such as high fever, rash, or headache occur. A physician should be consulted if the illness lasts more than 5 days despite treatment.

Gastrointestinal: Occasional patients may develop gastrointestinal disturbances and abdominal pain. It is possible in rare instances that chlorzoxazone may have been associated with gastrointestinal bleeding. Codeine has been known to cause constipation after long-term use.

CNS: Drowsiness, dizziness, lightheadedness, sedation, shortness of breath, nausea and vomiting, malaise, or overstimulation may be noted by an occasional patient. These effects seem to be more prominent in ambulatory than nonambulatory patients and some of these adverse effects may be alleviated if the patient lies down.

Allergic: Rarely, allergic-type skin rashes, petechiae, or ecchymoses may develop during treatment. Angioneurotic edema or anaphylactic reactions are extremely rare.

Renal Toxicity: 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.

Hepatotoxicity: 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 or bilirubin).

In a controlled multidose clinical trial with chlorzoxazone 500 mg, the following adverse events occurred in ³1% of patients receiving chlorzoxazone or occurred in <1% of patients but resulted in patient withdrawal from the study and were considered possibly, probably or definitely related to chlorzoxazone.

Body as a Whole: asthenia (2%), body pain, edema.

CNS: anxiety, dizziness (6%), drowsiness (9%), headache (5%), nervousness, paresthesia, vertigo.

Gastrointestinal: abnormal pain, anorexia, diarrhea (2%), dyspepsia (1%), flatulence, melena, nausea (3%).

Skin: pruritus, rash, skin discoloration.

Urogenital: polyuria.

The following adverse reports occurred with a frequency of <1% and the relationship to chlorzoxazone remains undetermined: chills, tachycardia, vasodilation, abnormal think- ing, confusion, depression, emotional lability, hypotonia, insomnia, constipation, dry mouth, thirst, vomiting, cough increase, dyspnea, flu symptoms, rhinitis, sweating, increased urinary frequency, menorrhagia.

At higher doses codeine has most of the disadvantages of morphine including respiratory depression.

Symptoms And Treatment Of Overdose: Symptoms: Chlorzoxazone: Initially, gastrointestinal disturbances such as nausea, vomiting, or diarrhea together with drowsiness, dizziness, lightheadedness or headache may occur. Early in the course there may be malaise or sluggishness followed by marked loss of muscle tone, making voluntary movement impossible. The deep tendon reflexes may be decreased or absent. The sensorium remains intact, and there is no peripheral loss of sensation. Respiratory depression may occur with rapid, irregular respiration and intercostal and substernal retraction. The blood pressure is lowered, but shock has not been observed.

Acetaminophen: In acute acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious effect. Renal tubular necrosis, hypoglycemia, coma, and thrombocytopenia may also occur. In adults, hepatotoxicity from acetaminophen is unlikely to occur with overdoses of less than 10 g ingested at one time and fatalities are unlikely to occur with overdoses of less than 15 g ingested at one time. Importantly, young children seem to be more resistant than adults to the hepatotoxic effect of an acetaminophen overdose. Despite this, the measures outlined below should be initiated in any adult or child suspected of having ingested an acetaminophen overdose.

Early symptoms following a potentially hepatotoxic overdose may include gastrointestinal irritability, nausea, vomiting, anorexia, diaphoresis and general malaise. However, the early clinical presentation of acetaminophen overdose is nonspecific and symptoms may even be lacking. A high index of suspicion for acetaminophen ingestion is required. Clinical and laboratory evidence of hepatic toxicity may not become evident until 48 to 72 hours post-ingestion.

Codeine: Serious overdose with codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse and death may occur.

Treatment: Chlorzoxazone: Appropriate gastrointestinal tract decontamination procedures should be undertaken. Thereafter treatment is entirely supportive. If consciousness is impaired, institute measures to protect the airway. If respiration is impaired, ventilation of the patient may be required. Blood pressure and tissue perfusion should be monitored and maintained by the usual technique. Cholinergic drugs or analeptic drugs are of no value and should not be used.

Acetaminophen: Appropriate gastrointestinal tract decontamination procedures should be implemented. Patients' estimates of the quantity of drug ingested are notoriously unreliable. Therefore, if an acetaminophen overdose is suspected, a serum acetaminophen assay should be obtained as early as possible, but no sooner than 4 hours following ingestion. Liver function studies should be obtained initially and repeated at 24-hour intervals.

The antidote, N-acetylcysteine, should be administered as early as possible, preferably within 16 hours of ingestion of the overdosage, but in any case, within 24 hours. Following recovery, there are no residual, structural or functional hepatic abnormalities.

Further information on the clinical course of acetaminophen overdose and its treatment with N-acetylcysteine is available from a Regional Poison Control Centre.

Codeine: Primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The narcotic antagonist naloxone is a specific antidote against respiratory depressions which may result from overdosage or unusual sensitivity to narcotics, including codeine. Therefore, an appropriate dose of naloxone should be administered, preferably by the i.v. route, and simultaneously with efforts at respiratory resuscitation. Since the duration of action of codeine may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration.

An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Oxygen, i.v. fluids, vasopressors and other supportive measures should be employed as indicated.

Dosage: The recommended adult dose is 1 to 2 tablets 4 times daily not to exceed 8 tablets in a 24-hour period.

Availability And Storage: Each round, hard, uncoated, biconvex, pink and white speckled tablet imprinted "PARAFON FORTE C8" on one side and "M" on the reverse, contains: chlorzoxazone 250 mg, acetaminophen 300 mg and codeine phosphate 8 mg. Nonmedicinal ingredients: cornstarch, FD&C Red No. 2, magnesium stearate and sodium lauryl sulfate. Energy: 0.889 kJ (0.211 kcal). Gluten-, lactose- and tartrazine-free. Bottles of 20 and 100. Protect from light in a tightly closed container. Under normal storage conditions at room temperature, tablets are stable for 2 years from date of manufacture.