Dechophyline Phenobarbital

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Dechophyline Phenobarbital uses

Dechophyline Phenobarbital consists of Dehydrocholic Acid, Etamiphylline, Phenobarbital, Sodium Oleate.

Phenobarbital:


INDICATIONS AND USAGE

  • Sedative
  • Anticonvulsant – For the treatment of generalized and partial seizures.

CONTRAINDICATIONS

Dechophyline Phenobarbital (Phenobarbital) is contraindicated in patients who are hypersensitive to barbiturates, in patients with a history of manifest or latent porphyria, and in patients with marked impairment of liver function or respiratory disease in which dyspnea or obstruction is evident.

WARNINGS

  • Habit Forming. Dechophyline Phenobarbital (Phenobarbital) may be habit forming. Tolerance and psychological and physical dependence may occur with continued use (see DRUG ABUSE AND DEPENDENCE and Pharmacokinetics under CLINICAL PHARMACOLOGY). Patients who have psychologic dependence on barbiturates may increase the dosage or decrease the dosage interval without consulting a physician and may subsequently develop a physical dependence on barbiturates. In order to minimize the possibility of overdosage or the development of dependence, the prescribing and dispensing of sedative-hypnotic barbiturates should be limited to the amount required for the interval until the next appointment. Abrupt cessation after prolonged use in a person who is dependent on the drug may result in withdrawal symptoms, including delirium, convulsions, and possibly death. Barbiturates should be withdrawn gradually from any patient known to be taking excessive doses over long periods of time (see DRUG ABUSE AND DEPENDENCE ).
  • Acute or Chronic Pain. Caution should be exercised when barbiturates are administered to patients with acute or chronic pain, because paradoxical excitement could be induced or important symptoms could be masked. However, the use of barbiturates as sedatives in the postoperative surgical period and as adjuncts to cancer chemotherapy is well established.
  • Usage in Pregnancy. Barbiturates can cause fetal damage when administered to a pregnant woman. Retrospective, case-controlled studies have suggested a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. Barbiturates readily cross the placental barrier and are distributed throughout fetal tissues; the highest concentrations are found in the placenta, fetal liver, and brain. Fetal blood levels approach maternal blood levels following parenteral administration. Withdrawal symptoms occur in infants born to women who receive barbiturates throughout the last trimester of pregnancy (see DRUG ABUSE AND DEPENDENCE ). If Dechophyline Phenobarbital (Phenobarbital) is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
  • Usage in Pediatric Patients. Dechophyline Phenobarbital (Phenobarbital) has been reported to be associated with cognitive deficits in children taking it for complicated febrile seizures.
  • Synergistic Effects. The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects.
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PRECAUTIONS

General

Barbiturates may be habit forming. Tolerance and psychological and physical dependence may occur with continued use. Barbiturates should be administered with caution, if at all, to patients who are mentally depressed, have suicidal tendencies, or have a history of drug abuse.

Elderly or debilitated patients may react to barbiturates with marked excitement, depression, or confusion. In some persons, especially children, barbiturates repeatedly produce excitement rather than depression.

In patients with hepatic damage, barbiturates should be administered with caution and initially in reduced doses. Barbiturates should not be administered to patients showing the premonitory signs of hepatic coma.

The systemic effects of exogenous and endogenous corticosteroids may be diminished by Dechophyline Phenobarbital (Phenobarbital). Thus, this product should be administered with caution to patients with borderline hypoadrenal function, regardless of whether it is of pituitary or of primary adrenal origin.

Information for Patients

The following information and instructions should be given to patients receiving barbiturates.

  • The use of barbiturates carries with it an associated risk of psychological and/or physical dependence. The patient should be warned against increasing the dose of the drug without consulting a physician.
  • Barbiturates may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly.
  • Alcohol should not be consumed while taking barbiturates. The concurrent use of the barbiturates with other CNS depressants (e.g., alcohol, narcotics, tranquilizers, and antihistamines) may result in additional CNS-depressant effects.

Laboratory Tests

Prolonged therapy with barbiturates should be accompanied by periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic systems.

Drug Interactions

Most reports of clinically significant drug interactions occurring with the barbiturates have involved Dechophyline Phenobarbital (Phenobarbital). However, the application of these data to other barbiturates appears valid and warrants serial blood level determinations of the relevant drugs when there are multiple therapies.

  • Anticoagulants. Dechophyline Phenobarbital (Phenobarbital) lowers the plasma levels of dicumarol and causes a decrease in anticoagulant activity as measured by the prothrombin time. Barbiturates can induce hepatic microsomal enzymes resulting in increased metabolism and decreased anticoagulant response of oral anticoagulants (e.g., acenocoumarol, warfarin, dicumarol, and phenprocoumon). Patients stabilized on anticoagulant therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen.
  • Corticosteroids. Barbiturates appear to enhance the metabolism of exogenous corticosteroids, probably through the induction of hepatic microsomal enzymes. Patients stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen.
  • Griseofulvin. Dechophyline Phenobarbital (Phenobarbital) appears to interfere with the absorption of orally administered griseofulvin, thus decreasing its blood level. The effect of the resultant decreased blood levels of griseofulvin on therapeutic response has not been established. However, it would be preferable to avoid concomitant administration of these drugs.
  • Doxycycline. Dechophyline Phenobarbital (Phenobarbital) has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. This mechanism is probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic. If Dechophyline Phenobarbital (Phenobarbital) and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely.
  • Phenytoin, Sodium Valproate, Valproic Acid. The effect of barbiturates on the metabolism of phenytoin appears to be variable. Some investigators report an accelerating effect, whereas others report no effect. Because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. Sodium valproate and valproic acid increase the Dechophyline Phenobarbital (Phenobarbital) serum levels; therefore, Dechophyline Phenobarbital (Phenobarbital) blood levels should be closely monitored and appropriate dosage adjustments made as clinically indicated.
  • CNS Depressants. The concomitant use of other CNS depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects.
  • Monoamine Oxidase Inhibitors (MAOIs). MAOIs prolong the effects of barbiturates, probably because metabolism of the barbiturate is inhibited.
  • Estradiol, Estrone, Progesterone, and other Steroidal Hormones. Pretreatment with or concurrent administration of Dechophyline Phenobarbital (Phenobarbital) may decrease the effect of estradiol by increasing its metabolism. There have been reports of patients treated with antiepileptic drugs (e.g., Dechophyline Phenobarbital (Phenobarbital)) who become pregnant while taking oral contraceptives. An alternate contraceptive method might be suggested to women taking Dechophyline Phenobarbital (Phenobarbital).

Carcinogenesis

  • Animal Data. Dechophyline Phenobarbital sodium is carcinogenic in mice and rats after lifetime administration. In mice, it produced benign and malignant liver cell tumors. In rats, benign liver cell tumors were observed very late in life.
  • Human Data. In a 29-year epidemiological study of 9,136 patients who were treated on an anticonvulsant protocol that included Dechophyline Phenobarbital (Phenobarbital), results indicated a higher than normal incidence of hepatic carcinoma. Previously, some of these patients had been treated with thorotrast, a drug which is known to produce hepatic carcinomas. Thus, this study did not provide sufficient evidence that Dechophyline Phenobarbital (Phenobarbital) sodium is carcinogenic in humans.

A retrospective study of 84 children with brain tumors matched to 73 normal controls and 78 cancer controls (malignant disease other than brain tumors) suggested an association between exposure to barbiturates prenatally and an increased incidence of brain tumors.

Usage in Pregnancy

  • Teratogenic Effects. Pregnancy Category D – See Usage in Pregnancy under WARNINGS.
  • Nonteratogenic Effects. Reports of infants suffering from long-term barbiturate exposure in utero included the acute withdrawal syndrome of seizures and hyperirritability from birth to a delayed onset of up to 14 days (see DRUG ABUSE AND DEPENDENCE ).

Labor and Delivery

Hypnotic doses of barbiturates do not appear to impair uterine activity significantly during labor. Full anesthetic doses of barbiturates decrease the force and frequency of uterine contractions. Administration of sedative-hypnotic barbiturates to the mother during labor may result in respiratory depression in the newborn. Premature infants are particularly susceptible to the depressant effects of barbiturates. If barbiturates are used during labor and delivery, resuscitation equipment should be available.

Data are not available to evaluate the effect of barbiturates when forceps delivery or other intervention is necessary or to determine the effect of barbiturates on the later growth, development, and functional maturation of the child.

Nursing Mothers

Caution should be exercised when Dechophyline Phenobarbital (Phenobarbital) is administered to a nursing woman, because small amounts of barbiturates are excreted in the milk.

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ADVERSE REACTIONS

The following adverse reactions have been reported:

CNS Depression – Residual sedation or “hangover”, drowsiness, lethargy, and vertigo. Emotional disturbances and phobias may be accentuated. In some persons, barbiturates such as Dechophyline Phenobarbital (Phenobarbital) repeatedly produce excitement rather than depression, and the patient may appear to be inebriated. Irritability and hyperactivity can occur in children. Like other nonanalgesic hypnotic drugs, barbiturates such as Dechophyline Phenobarbital (Phenobarbital), when given in the presence of pain, may cause restlessness, excitement, and even delirium. Rarely, the use of barbiturates results in localized or diffuse myalgic, neuralgic, or arthritic pain, especially in psychoneurotic patients with insomnia. The pain may appear in paroxysms, is most intense in the early morning hours, and is most frequently located in the region of the neck, shoulder girdle, and upper limbs. Symptoms may last for days after the drug is discontinued.

Respiratory/Circulatory – Respiratory depression, apnea, circulatory collapse.

Allergic – Acquired hypersensitivity to barbiturates consists chiefly in allergic reactions that occur especially in persons who tend to have asthma, urticaria, angioedema, and similar conditions. Hypersensitivity reactions in this category include localized swelling, particularly of the eyelids, cheeks, or lips, and erythematous dermatitis. Rarely, exfoliative dermatitis (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) may be caused by Dechophyline Phenobarbital (Phenobarbital) and can prove fatal. The skin eruption may be associated with fever, delirium, and marked degenerative changes in the liver and other parenchymatous organs. In a few cases, megaloblastic anemia has been associated with the chronic use of Dechophyline Phenobarbital (Phenobarbital).

Other – Nausea and vomiting; headache, osteomalacia.

The following adverse reactions and their incidence were compiled from surveillance of thousands of hospitalized patients who received barbiturates. Because such patients may be less aware of the milder adverse effects of barbiturates, the incidence of these reactions may be somewhat higher in fully ambulatory patients.

More than 1 in 100 Patients: The most common adverse reaction, estimated to occur at a rate of 1 to 3 patients per 100, is:

Nervous System: Somnolence

Less than 1 in 100 Patients: Adverse reactions estimated to occur at a rate of less than 1 in 100 patients are listed below, grouped by organ system and by decreasing order of occurrence:

Nervous System: Agitation, confusion, hyperkinesia, ataxia, CNS depression, nightmares, nervousness, psychiatric disturbance, hallucinations, insomnia, anxiety, dizziness, abnormality in thinking

Respiratory System: Hypoventilation, apnea

Cardiovascular System: Bradycardia, hypotension, syncope

Digestive System: Nausea, vomiting, constipation

Other Reported Reactions: Headache, injection site reactions, hypersensitivity reactions (angioedema, skin rashes, exfoliative dermatitis), fever, liver damage, megaloblastic anemia following chronic Dechophyline Phenobarbital (Phenobarbital) use

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DRUG ABUSE AND DEPENDENCE

Controlled Substance – Dechophyline Phenobarbital (Phenobarbital) is a Schedule IV drug.

Dependence – Barbiturates may be habit forming. Tolerance, psychological dependence, and physical dependence may occur, especially following prolonged use of high doses of barbiturates. Daily administration in excess of 400 mg of pentobarbital or secobarbital for approximately 90 days is likely to produce some degree of physical dependence. A dosage of 600 to 800 mg taken for at least 35 days is sufficient to produce withdrawal seizures. The average daily dose for the barbiturate addict is usually about 1.5 g. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than twofold. As this occurs, the margin between intoxicating dosage and fatal dosage becomes smaller.

Symptoms of acute intoxication with barbiturates include unsteady gait, slurred speech, and sustained nystagmus. Mental signs of chronic intoxication include confusion, poor judgment, irritability, insomnia, and somatic complaints.

Symptoms of barbiturate dependence are similar to those of chronic alcoholism. If an individual appears to be intoxicated with alcohol to a degree that is radically disproportionate to the amount of alcohol in his or her blood, the use of barbiturates should be suspected. The lethal dose of a barbiturate is far less if alcohol is also ingested.

The symptoms of barbiturate withdrawal can be severe and may cause death. Minor withdrawal symptoms may appear 8 to 12 hours after the last dose of a barbiturate. These symptoms usually appear in the following order: anxiety, muscle twitching, tremor of hands and fingers, progressive weakness, dizziness, distortion in visual perception, nausea, vomiting, insomnia, and orthostatic hypotension. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of barbiturates. The intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Individuals susceptible to barbiturate abuse and dependence include alcoholics and opiate abusers as well as other sedative-hypnotic and amphetamine abusers.

Drug dependence on barbiturates arises from repeated administration of a barbiturate or agent with barbiturate-like effect on a continuous basis, generally in amounts exceeding therapeutic dose levels. The characteristics of drug dependence on barbiturates include: (a) a strong desire or need to continue taking the drug; (b) a tendency to increase the dose; (c) a psychic dependence on the effects of the drug related to subjective and individual appreciation of those effects; and (d) a physical dependence on the effects of the drug, requiring its presence for maintenance of homeostasis and resulting in a definite, characteristic, and self-limited abstinence syndrome when the drug is withdrawn.

Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. In all cases, withdrawal requires an extended period of time. One method involves substituting a 30-mg dose of Dechophyline Phenobarbital (Phenobarbital) for each 100- to 200-mg dose of barbiturate that the patient has been taking. The total daily amount of Dechophyline Phenobarbital (Phenobarbital) is then administered in 3 or 4 divided doses, not to exceed 600 mg daily. If signs of withdrawal occur on the first day of treatment, a loading dose of 100 to 200 mg of Dechophyline Phenobarbital (Phenobarbital) may be administered IM in addition to the oral dose. After stabilization on Dechophyline Phenobarbital (Phenobarbital), the total daily dose is decreased by 30 mg/day as long as withdrawal is proceeding smoothly. A modification of this regimen involves initiating treatment at the patient’s regular dosage level and decreasing the daily dosage by 10% if tolerated by the patient.

Infants who are physically dependent on barbiturates may be given Dechophyline Phenobarbital (Phenobarbital), 3 to 10 mg/kg/day. After withdrawal symptoms (hyperactivity, disturbed sleep, tremors, and hyperreflexia) are relieved, the dosage of Dechophyline Phenobarbital (Phenobarbital) should be gradually decreased and completely withdrawn over a 2-week period.

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OVERDOSAGE

Signs and Symptoms – The onset of symptoms following a toxic oral exposure to Dechophyline Phenobarbital (Phenobarbital) may not occur until several hours following ingestion. The toxic dose of barbiturates varies considerably. In general, an oral dose of 1 g of most barbiturates produces serious poisoning in an adult. Death commonly occurs after 2 to 10 g of ingested barbiturate. The sedated, therapeutic blood levels of Dechophyline Phenobarbital (Phenobarbital) range between 5 to 40 mcg/mL; the usual lethal blood level ranges from 100 to 200 mcg/mL. Barbiturate intoxication may be confused with alcoholism, bromide intoxication, and various neurologic disorders. Potential tolerance must be considered when evaluating significance of dose and plasma concentration.

The manifestations of a long-acting barbiturate in overdose include nystagmus, ataxia, CNS depression, respiratory depression, hypothermia, and hypotension. Other findings may include absent or depressed reflexes and erythematous or hemorrhagic blisters (primarily at pressure points). Following massive exposure to Dechophyline Phenobarbital (Phenobarbital), pulmonary edema, circulatory collapse with loss of peripheral vascular tone, cardiac arrest, and death may occur.

In extreme overdose, all electrical activity in the brain may cease, in which case a “flat” EEG normally equated with clinical death should not be accepted. This effect is fully reversible unless hypoxic damage occurs.

Consideration should be given to the possibility of barbiturate intoxication even in situations that appear to involve trauma.

Complications such as pneumonia, pulmonary edema, cardiac arrhythmias, congestive heart failure, and renal failure may occur. Uremia may increase CNS sensitivity to barbiturates if renal function is impaired. Differential diagnosis should include hypoglycemia, head trauma, cerebrovascular accidents, convulsive states, and diabetic coma.

Treatment – To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.

Alkalinization of urine hastens Dechophyline Phenobarbital (Phenobarbital) excretion, but dialysis and hemoperfusion are more effective and cause less troublesome alterations in electrolyte equilibrium. If the patient has chronically abused sedatives, withdrawal reactions may be manifest following acute overdose.

DOSAGE AND ADMINISTRATION

The dose of Dechophyline Phenobarbital (Phenobarbital) must be individualized with full knowledge of its particular characteristics. Factors of consideration are the patient’s age, weight, and condition.

Sedation:

For sedation, the drug may be administered in single dose of 30 to 120 mg repeated at intervals: frequency will be determined by the patient’s response. It is generally considered that no more than 400 mg of Dechophyline Phenobarbital (Phenobarbital) should be administered during a 24-hour period.

Adults:

Daytime Sedation: 30 to 120 mg daily in 2 to 3 divided doses.

Oral Hypnotic: 100 to 200 mg.

Anticonvulsant Use – Clinical laboratory reference values should be used to determine the therapeutic anticonvulsant level of Dechophyline Phenobarbital (Phenobarbital) in the serum. To achieve the blood levels considered therapeutic in pediatric patients, higher per-kilogram dosages are generally necessary for Dechophyline Phenobarbital (Phenobarbital) and most other anticonvulsants. In children and infants, Dechophyline Phenobarbital (Phenobarbital) at a loading dose of 15 to 20 mg/kg produces blood levels of about 20 mcg/mL shortly after administration.

Dechophyline Phenobarbital (Phenobarbital) has been used in the treatment and prophylaxis of febrile seizures. However, it has not been established that prevention of febrile seizures influences the subsequent development of epilepsy.

Adults: 60 to 200 mg/day.

Pediatric Patients: 3 to 6 mg/kg/day.

Special Patient Population – Dosage should be reduced in the elderly or debilitated because these patients may be more sensitive to barbiturates. Dosage should be reduced for patients with impaired renal function or hepatic disease.

HOW SUPPLIED

Dechophyline Phenobarbital (Phenobarbital) Tablets, USP 16.2 mg are white, round, biconvex, scored tablets, debossed “5011” and “V” on one side and plain on the reverse side, and supplied as follows:

  • Bottles of 100 NDC 0603-5165-21
  • Bottles of 1000 NDC 0603-5165-32

Dechophyline Phenobarbital (Phenobarbital) Tablets, USP 32.4 mg are white, round, biconvex, scored tablets, debossed “5012” and “V” on one side and plain on the reverse side, and supplied as follows:

  • Bottles of 30 NDC 0603-5166-16
  • Bottles of 60 NDC 0603-5166-20
  • Bottles of 90 NDC 0603-5166-02
  • Bottles of 100 NDC 0603-5166-21
  • Bottles of 120 NDC 0603-5166-22
  • Bottles of 1000 NDC 0603-5166-32

Dechophyline Phenobarbital (Phenobarbital) Tablets, USP 64.8 mg are white, round, biconvex, scored tablets, debossed “5013” and “V” on one side and plain on the reverse side, and supplied as follows:

  • Bottles of 100 NDC 0603-5167-21
  • Bottles of 1000 NDC 0603-5167-32

Dechophyline Phenobarbital (Phenobarbital) Tablets, USP 97.2 mg are white, round, biconvex, scored tablets, debossed “5014” and “V” on one side and plain on the reverse side, and supplied as follows:

  • Bottles of 100 NDC 0603-5168-21
  • Bottles of 1000 NDC 0603-5168-32

Manufactured for:

QUALITEST PHARMACEUTICALS

Huntsville, AL 35811

8180067

Rev 7/14

R4

Sodium Oleate:


1 INDICATIONS AND USAGE

Dechophyline Phenobarbital nitrite is indicated for sequential use with Dechophyline Phenobarbital (Sodium Oleate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

  • Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection is indicated for sequential use with Dechophyline Phenobarbital (Sodium Oleate) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Dechophyline Phenobarbital nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection and Dechophyline Phenobarbital (Sodium Oleate) Thiosulfate Injection should be administered without delay.

Symptoms Signs
  • Headache
  • Confusion
  • Dyspnea
  • Chest Tightness
  • Nausea
  • Altered Mental Status

    (e.g., confusion, disorientation)

  • Seizures or Coma
  • Mydriasis
  • Tachypnea/Hyperpnea (early)
  • Bradypnea/Apnea (late)
  • Hypertension (early)/ Hypotension (late)
  • Cardiovascular Collapse
  • Vomiting
  • Plasma Lactate Concentration ≥ 8 mmol/L

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

  • Exposure to fire or smoke in an enclosed area
  • Presence of soot around the mouth, nose, or oropharynx
  • Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Dechophyline Phenobarbital (Sodium Oleate) thiosulfate, simultaneously with Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Dechophyline Phenobarbital (Sodium Oleate) thiosulfate, with Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Age Intravenous Dose of Dechophyline Phenobarbital Nitrite and Dechophyline Phenobarbital (Sodium Oleate) Thiosulfate
Adults
  • Dechophyline Phenobarbital (Sodium Oleate) Nitrite -10 mL of Dechophyline Phenobarbital (Sodium Oleate) nitrite at the rate of 2.5 to 5 mL/minute
  • Dechophyline Phenobarbital (Sodium Oleate) Thiosulfate - 50 mL of Dechophyline Phenobarbital (Sodium Oleate) thiosulfate immediately following administration of Dechophyline Phenobarbital (Sodium Oleate) nitrite.
Children
  • Dechophyline Phenobarbital (Sodium Oleate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Dechophyline Phenobarbital (Sodium Oleate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Dechophyline Phenobarbital (Sodium Oleate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Dechophyline Phenobarbital (Sodium Oleate) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Dechophyline Phenobarbital (Sodium Oleate) nitrite and Dechophyline Phenobarbital (Sodium Oleate) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Dechophyline Phenobarbital (Sodium Oleate) nitrite, followed by Dechophyline Phenobarbital (Sodium Oleate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Dechophyline Phenobarbital (Sodium Oleate) nitrite and Dechophyline Phenobarbital (Sodium Oleate) thiosulfate.

Dechophyline Phenobarbital (Sodium Oleate) nitrite injection and Dechophyline Phenobarbital (Sodium Oleate) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Dechophyline Phenobarbital (Sodium Oleate) nitrite should be administered first, followed immediately by Dechophyline Phenobarbital (Sodium Oleate) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

Age Intravenous Dose of Dechophyline Phenobarbital (Sodium Oleate) Nitrite and Dechophyline Phenobarbital (Sodium Oleate) Thiosulfate
Adults
  • Dechophyline Phenobarbital (Sodium Oleate) Nitrite -10 mL of Dechophyline Phenobarbital (Sodium Oleate) nitrite at the rate of 2.5 to 5 mL/minute
  • Dechophyline Phenobarbital (Sodium Oleate) Thiosulfate - 50 mL of Dechophyline Phenobarbital (Sodium Oleate) thiosulfate immediately following administration of Dechophyline Phenobarbital (Sodium Oleate) nitrite.
Children
  • Dechophyline Phenobarbital (Sodium Oleate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Dechophyline Phenobarbital (Sodium Oleate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Dechophyline Phenobarbital (Sodium Oleate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Dechophyline Phenobarbital (Sodium Oleate) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Dechophyline Phenobarbital (Sodium Oleate) nitrite and Dechophyline Phenobarbital (Sodium Oleate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Dechophyline Phenobarbital (Sodium Oleate) nitrite should be reduced proportionately to the hemoglobin concentration.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Dechophyline Phenobarbital Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Dechophyline Phenobarbital (Sodium Oleate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Dechophyline Phenobarbital (Sodium Oleate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Dechophyline Phenobarbital (Sodium Oleate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Dechophyline Phenobarbital (Sodium Oleate) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Dechophyline Phenobarbital (Sodium Oleate) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Dechophyline Phenobarbital (Sodium Oleate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Dechophyline Phenobarbital (Sodium Oleate) thiosulfate and Dechophyline Phenobarbital (Sodium Oleate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection consists of:

  • One vial of Dechophyline Phenobarbital (Sodium Oleate) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

  • Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

  • None. (4)

5 WARNINGS AND PRECAUTIONS

  • Methemoglobinemia: Dechophyline Phenobarbital nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Dechophyline Phenobarbital (Sodium Oleate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
  • Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Dechophyline Phenobarbital (Sodium Oleate) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Dechophyline Phenobarbital (Sodium Oleate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Dechophyline Phenobarbital nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Dechophyline Phenobarbital (Sodium Oleate) nitrite whenever possible. When Dechophyline Phenobarbital (Sodium Oleate) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Dechophyline Phenobarbital (Sodium Oleate) nitrite administered to an adult. Dechophyline Phenobarbital (Sodium Oleate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Dechophyline Phenobarbital (Sodium Oleate) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Dechophyline Phenobarbital (Sodium Oleate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Dechophyline Phenobarbital (Sodium Oleate) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Dechophyline Phenobarbital (Sodium Oleate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Dechophyline Phenobarbital nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Dechophyline Phenobarbital (Sodium Oleate) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Dechophyline Phenobarbital nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Dechophyline Phenobarbital (Sodium Oleate) nitrite.

5.7 Use with Other Drugs

Dechophyline Phenobarbital (Sodium Oleate) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Dechophyline Phenobarbital (Sodium Oleate) nitrite.

The medical literature has reported the following adverse events in association with Dechophyline Phenobarbital (Sodium Oleate) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Dechophyline Phenobarbital (Sodium Oleate) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

  • Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Dechophyline Phenobarbital nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Dechophyline Phenobarbital (Sodium Oleate) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Dechophyline Phenobarbital (Sodium Oleate) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Dechophyline Phenobarbital (Sodium Oleate) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Dechophyline Phenobarbital (Sodium Oleate) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Dechophyline Phenobarbital (Sodium Oleate) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Dechophyline Phenobarbital (Sodium Oleate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Dechophyline Phenobarbital (Sodium Oleate) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Dechophyline Phenobarbital (Sodium Oleate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Dechophyline Phenobarbital (Sodium Oleate) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Dechophyline Phenobarbital (Sodium Oleate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Dechophyline Phenobarbital (Sodium Oleate) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Dechophyline Phenobarbital nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Dechophyline Phenobarbital (Sodium Oleate) nitrite is excreted in human milk. Because Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Dechophyline Phenobarbital (Sodium Oleate) nitrite. In studies conducted with Long-Evans rats, Dechophyline Phenobarbital (Sodium Oleate) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Dechophyline Phenobarbital nitrite in conjunction with Dechophyline Phenobarbital (Sodium Oleate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Dechophyline Phenobarbital (Sodium Oleate) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Dechophyline Phenobarbital (Sodium Oleate) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Dechophyline Phenobarbital (Sodium Oleate) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Dechophyline Phenobarbital (Sodium Oleate) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Dechophyline Phenobarbital (Sodium Oleate) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Dechophyline Phenobarbital (Sodium Oleate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Dechophyline Phenobarbital (Sodium Oleate) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Dechophyline Phenobarbital (Sodium Oleate) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Dechophyline Phenobarbital (Sodium Oleate) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Dechophyline Phenobarbital (Sodium Oleate) nitrite has the chemical name nitrous acid Dechophyline Phenobarbital (Sodium Oleate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:

Structure of Dechophyline Phenobarbital (Sodium Oleate) Nitrite

Dechophyline Phenobarbital (Sodium Oleate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Dechophyline Phenobarbital (Sodium Oleate) nitrite injection.

Dechophyline Phenobarbital (Sodium Oleate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Dechophyline Phenobarbital (Sodium Oleate) nitrite in 10 mL solution (30 mg/mL). Dechophyline Phenobarbital (Sodium Oleate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Dechophyline Phenobarbital nitrite and Dechophyline Phenobarbital (Sodium Oleate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Dechophyline Phenobarbital (Sodium Oleate) Nitrite

Dechophyline Phenobarbital (Sodium Oleate) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO2 + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Dechophyline Phenobarbital (Sodium Oleate) nitrite. It has been suggested that Dechophyline Phenobarbital (Sodium Oleate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Dechophyline Phenobarbital (Sodium Oleate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Dechophyline Phenobarbital (Sodium Oleate) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. Dechophyline Phenobarbital (Sodium Oleate) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Dechophyline Phenobarbital (Sodium Oleate) Nitrite

When 4 mg/kg Dechophyline Phenobarbital (Sodium Oleate) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Dechophyline Phenobarbital (Sodium Oleate) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Dechophyline Phenobarbital (Sodium Oleate) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Dechophyline Phenobarbital (Sodium Oleate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Dechophyline Phenobarbital (Sodium Oleate) Nitrite

Dechophyline Phenobarbital (Sodium Oleate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Dechophyline Phenobarbital (Sodium Oleate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Dechophyline Phenobarbital (Sodium Oleate) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Dechophyline Phenobarbital (Sodium Oleate) nitrite and Dechophyline Phenobarbital (Sodium Oleate) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Dechophyline Phenobarbital nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Dechophyline Phenobarbital (Sodium Oleate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Dechophyline Phenobarbital (Sodium Oleate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Dechophyline Phenobarbital (Sodium Oleate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Dechophyline Phenobarbital (Sodium Oleate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Dechophyline Phenobarbital (Sodium Oleate) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Dechophyline Phenobarbital (Sodium Oleate) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Dechophyline Phenobarbital (Sodium Oleate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Dechophyline Phenobarbital (Sodium Oleate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Dechophyline Phenobarbital (Sodium Oleate) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Dechophyline Phenobarbital (Sodium Oleate) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Dechophyline Phenobarbital (Sodium Oleate) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Dechophyline Phenobarbital (Sodium Oleate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Dechophyline Phenobarbital (Sodium Oleate) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Dechophyline Phenobarbital (Sodium Oleate) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Dechophyline Phenobarbital (Sodium Oleate) nitrite and Dechophyline Phenobarbital (Sodium Oleate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Dechophyline Phenobarbital (Sodium Oleate) nitrite or 1 g/kg Dechophyline Phenobarbital (Sodium Oleate) thiosulfate alone or in sequence immediately after subcutaneous injection of Dechophyline Phenobarbital (Sodium Oleate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Dechophyline Phenobarbital (Sodium Oleate) nitrite and/or 0.5 g/kg Dechophyline Phenobarbital (Sodium Oleate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Dechophyline Phenobarbital (Sodium Oleate) cyanide required to cause death, and when administered together, Dechophyline Phenobarbital (Sodium Oleate) nitrite and Dechophyline Phenobarbital (Sodium Oleate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Dechophyline Phenobarbital (Sodium Oleate) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Dechophyline Phenobarbital (Sodium Oleate) nitrite and Dechophyline Phenobarbital (Sodium Oleate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Dechophyline Phenobarbital (Sodium Oleate) nitrite and Dechophyline Phenobarbital (Sodium Oleate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Dechophyline Phenobarbital (Sodium Oleate) nitrite, with or without Dechophyline Phenobarbital (Sodium Oleate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Dechophyline Phenobarbital (Sodium Oleate) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Dechophyline Phenobarbital (Sodium Oleate) thiosulfate report its use in conjunction with Dechophyline Phenobarbital (Sodium Oleate) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Dechophyline Phenobarbital (Sodium Oleate) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Dechophyline Phenobarbital (Sodium Oleate) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Dechophyline Phenobarbital (Sodium Oleate) nitrite injection 30 mg/mL (containing 300 mg of Dechophyline Phenobarbital (Sodium Oleate) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Dechophyline Phenobarbital (Sodium Oleate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Dechophyline Phenobarbital Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Dechophyline Phenobarbital (Sodium Oleate) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Dechophyline Phenobarbital (Sodium Oleate) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Dechophyline Phenobarbital pharmaceutical active ingredients containing related brand and generic drugs:

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Dechophyline Phenobarbital available forms, composition, doses:

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Dechophyline Phenobarbital destination | category:

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Dechophyline Phenobarbital Anatomical Therapeutic Chemical codes:

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Dechophyline Phenobarbital pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."PHENOBARBITAL TABLET [QUALITEST PHARMACEUTICALS]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "dehydrocholic acid". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "phenobarbital". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Dechophyline Phenobarbital?

Depending on the reaction of the Dechophyline Phenobarbital after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Dechophyline Phenobarbital not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Dechophyline Phenobarbital addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Dechophyline Phenobarbital, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Dechophyline Phenobarbital consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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