Prescription Drugs

CLINICAL PHARMACOLOGY Meperidine hydrochloride is a narcotic analgesic with multiple actions qualitatively similar to those of morphine. Phenergan®, promethazine HCl, is a phenothiazine derivative that has several different pharmacologic properties including antihistaminic, sedative, and antiemetic actions.

DESCRIPTION This product is available in concentration providing 25 mg each of meperidine hydrochloride and promethazine hydrochloride per mL with 0.1 mg edetate disodium, 0.04 mg calcium chloride, and not more than 0.75 mg sodium formaldehyde sulfoxylate, 0.25 mg sodium metabisulfite, and 5 mg phenol with sodium acetate buffer.

INDICATIONS As a preanesthetic medication when analgesia and sedation are indicated. As an adjunct to local and general anesthesia. DOSAGE AND ADMINISTRATION Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. WARNING BARBITURATES ARE NOT CHEMICALLY COMPATIBLE IN SOLUTION WITH MEPERGAN (meperidine and promethazine) (MEPERIDINE HYDROCHLORIDE AND PROMETHAZINE HYDROCHLORIDE) AND SHOULD NOT BE MIXED IN THE SAME SYRINGE. Mepergan (meperidine and promethazine) is usually administered intramuscularly. However, in certain specific situations, the intravenous route may be employed. INADVERTENT INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY (see " Warnings "). SUBCUTANEOUS ADMINISTRATION IS CONTRAINDICATED, AS IT MAY RESULT IN TISSUE NECROSIS (see " Contraindications "). INJECTION INTO OR NEAR PERIPHERAL NERVES MAY RESULT IN PERMANENT NEUROLOGICAL DEFICIT. When used intravenously, the rate should not be greater than 1 mL of Mepergan (meperidine and promethazine) (25 mg of each component) per minute; it is preferable to inject through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. The TUBEX® BLUNT POINT™ Sterile Cartridge Unit is suitable for substances to be administered intravenously only. It is intended for use with injection sets specifically manufactured as "needle-less" injection systems. TUBEX® BLUNT POINT™ is compatible with Abbott's LifeShield® prepierced reseal injection site, Baxter's InterLink® Injection Site, and B. Braun Medical's SafSite® Reflux Valve, Consult manufacturer's recommendations regarding "Directions for Use" of the "needle-less" system. It is also intended for admixture with, and convenient administration of various medicaments when using Drug Vial Adapters for "needle-less" injection systems. The TUBEX® Sterile Cartridge-Needle Unit is suitable for substances to be administered intravenously or intramuscularly. The TUBEX® Sterile Cartridge-Needle Unit is designed for single-dose use. VIALS should be used when required doses are fractions of a milliliter, as indicated below. ADULT DOSE: 1 to 2 mL (25 to 50 mg of each component) per single injection, which can be repeated every 3 to 4 hours. CHILDREN 12 YEARS OF AGE AND UNDER: 0.5 mg of each component per pound of body weight. The dosage may be repeated every 3 to 4 hours as necessary. For preanesthetic medication the usual adult dose is 2 mL (50 mg of each component) intramuscularly with or without appropriate atropine-like drug. Atropine sulfate, 0.3 to 0.4 mg, or scopolamine hydrobromide, 0.25 to 0.4 mg, in sterile solution may be mixed in the same syringe with Mepergan (meperidine and promethazine) . Repeat doses of 50 mg or less of both promethazine and meperidine may be administered by either route at 3- to 4-hour intervals, as necessary. As an adjunct to local or general anesthesia, the usual dose is 2 mL (50 mg each of meperidine and promethazine). HOW SUPPLIED Mepergan (meperidine and promethazine) ® (meperidine HCl and promethazine HCl) Injection is available in TUBEX® BLUNT POINT™ Sterile Cartridge Units and Sterile Cartridge-Needle Units, in boxes of 10 TUBEX in TAMP-R-TEL® tamper-resistant packages as follows: NDC 0008-0235-50, 2 mL size Blunt Point™ NDC 0008-0235-01, 2 mL size (22 gauge x 1- 1 / 4 inch needle). Mepergan (meperidine and promethazine) (meperidine HCl and promethazine HCl) Injection is also available in vials as follows: NDC 0008-0234, 10 mL vial. Do not use if solution is discolored or contains a precipitate. Protect from light Use carton to protect contents from light Store at room temperature, approximately 25° C (77° F) Manufactured by: Wyeth Laboratories A Wyeth-Ayerst Company Philadelphia, PA 19101

PATIENT INFORMATION No Information Provided.

OVERDOSE SYMPTOMS Serious overdose with meperidine 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, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. TREATMENT Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. The narcotic antagonist, naloxone hydrochloride, is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to narcotics, including meperidine. The usual initial adult dose of naloxone is 0.4 to 2.0 mg, administered intravenously. If the desired degree of counteraction and improvement in respiratory functions is not obtained, this dosage can be repeated at two- to three-minute intervals while resuscitation efforts continue. If 10 mg of naloxone have been administered without an improvement in the clinical situation, the diagnosis of Mepergan (meperidine and promethazine) overdose should be questioned. An antagonist should not be administered in absence of clinically significant respiratory or cardiovascular depression. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. NOTE: In an individual physically dependent on narcotics, the administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of narcotic antagonists in such individuals should be avoided if possible. If a narcotic antagonist must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and only one-tenth to one-fifth the usual initial dose administered. Attempted suicides with promethazine have resulted in deep sedation, coma, rarely convulsions and cardiorespiratory symptoms compatible with the depth of sedation present. Extrapyramidal reactions may be treated with anticholinergic antiparkinson agents, diphenhydramine, or barbiturates. If severe hypotension occurs, levarterenol or phenylephrine may be indicated. Epinephrine is probably best avoided, since it has been suggested that promethazine overdosage could produce a partial alpha-adrenergic blockade. A paradoxical reaction, characterized by hyperexcitability and nightmares, has been reported in children receiving large single doses of promethazine. CONTRAINDICATIONS Hypersensitivity to meperidine or promethazine. Under no circumstances should Mepergan (meperidine and promethazine) be given by intra-arterial injection, due to the likelihood of severe arteriospasm and the possibility of resultant gangrene (see " WARNINGS"). Mepergan (meperidine and promethazine) should not be given by the subcutaneous route; evidence of chemical irritation has been noted, and necrotic lesions have resulted on rare occasions following subcutaneous injection. The preferred parenteral route of administration is by deep intramuscular injection. Meperidine is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOI) or those who have received such agents within 14 days. Therapeutic doses of meperidine have inconsistently precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension and have resembled the syndrome of acute narcotic overdose. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension. Although it is not known that other narcotics are free of the risk of such reactions, virtually all of the reported reactions have occurred with meperidine. If a narcotic is needed in such patients, a sensitivity test should be performed in which repeated, small, incremental doses of morphine are administered over the course of several hours while the patient's condition and vital signs are under careful observation. (Intravenous hydrocortisone or prednisolone have been used to treat severe reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown.)

SIDE EFFECTS The major hazards of meperidine, as with other narcotic analgesics, are respiratory depression and, to a lesser degree, circulatory depression; respiratory arrest, shock, and cardiac arrest have occurred. The most frequently observed adverse reactions include light-headedness, dizziness, sedation, nausea, vomiting, and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not experiencing severe pain. In such individuals, lower doses are advisable. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down. Other adverse reactions include: CENTRAL NERVOUS SYSTEM Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, transient hallucinations and disorientation, visual disturbances and, rarely, extrapyramidal reactions. GASTROINTESTINAL Dry mouth, constipation, biliary-tract spasm. CARDIOVASCULAR Flushing of the face, tachycardia, bradycardia, palpitation, faintness, syncope. Cardiovascular effects from promethazine have been rare. Minor increases in blood pressure and occasional mild hypotension have been reported. Venous thrombosis at the injection site has been reported. Intra-arterial injection of Mepergan (meperidine and promethazine) may result in gangrene of the affected extremity (see " WARNINGS"). GENITOURINARY Urinary retention. ALLERGIC Pruritus, urticaria, other skin rashes, wheal and flare over the vein with IV injection. Photosensitivity, although extremely rare, has been reported. Occurrence of photosensitivity may be a contraindication to further treatment with promethazine or related drugs. OTHER Pain at injection site; local tissue irritation, induration, and possible tissue necrosis, particularly when injection is repeated at same site; antidiuretic effect. Patients may occasionally complain of autonomic reactions, such as dryness of the mouth, blurring of vision and, rarely, dizziness following the use of promethazine. Very rare cases have been reported where patients receiving promethazine have developed leukopenia. In one instance agranulocytosis has been reported. In nearly every instance reported, other toxic agents known to have caused these conditions have been associated with the administration of promethazine. DRUG INTERACTIONS No Information Provided.

WARNINGS Mepergan (meperidine and promethazine) Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. Tolerance and Addiction Liability Warning may be habit-forming DRUG DEPENDENCE Meperidine 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 meperidine, and it should be prescribed and administered with the same degree of caution appropriate to the use of morphine. Like other narcotics, meperidine is subject to the provisions of the Federal narcotic laws. INTERACTION WITH OTHER CENTRAL NERVOUS SYSTEM DEPRESSANTS Meperidine should be used with great caution and in reduced dosage in patients who are concurrently receiving other narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics, tricyclic antidepressants, and other CNS depressants (including alcohol). Respiratory depression, hypotension, and profound sedation or coma may result. The sedative action of promethazine hydrochloride is additive to the sedative effects of central nervous system depressants; therefore, agents such as alcohol, barbiturates, and narcotic analgesics should either be eliminated or given in reduced dosage in the presence of promethazine hydrochloride. When given concomitantly with promethazine hydrochloride, the dose of barbiturates should be reduced by at least one-half and the dose of analgesic depressants, such as morphine or meperidine, should be reduced by one-quarter to one-half. HEAD INJURY AND INCREASED INTRACRANIAL PRESSURE The respiratory-depressant effects of meperidine and its capacity to elevate cerebrospinal-fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. In such patients, meperidine must be used with extreme caution and only if its use is deemed essential. INADVERTENT INTRA-ARTERIAL INJECTION Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or inadvertent intra-arterial injection of Mepergan (meperidine and promethazine) . Reports compatible with inadvertent intra-arterial injection suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation is likely under such circumstances. Intravenous injection was intended in all the cases reported, but perivascular extravasation or arterial placement of the needle is now suspect. There is no proven successful management of this condition after it occurs, although sympathetic block and heparinization are commonly employed during the acute management because of the results of animal experiments with other known arteriolar irritants. Aspiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with promethazine. Use of syringes with rigid plungers or of small bore needles might obscure typical arterial backflow if this is relied upon alone. INTRAVENOUS USE If necessary, meperidine may be given intravenously, but the injection should be given very slowly, preferably in the form of a diluted solution. Rapid intravenous injection of narcotic analgesics, including meperidine, increases the incidence of adverse reactions; severe respiratory depression, apnea, hypotension, peripheral circulatory collapse, and cardiac arrest have occurred. Meperidine should not be administered intravenously unless a narcotic antagonist and the facilities for assisted or controlled respiration are immediately available. When meperidine is given parenterally, especially intravenously, the patient should be lying down. When used intravenously, Mepergan (meperidine and promethazine) should be given at a rate not to exceed 1 mL (25 mg of each component) per minute. When administering any irritant drug intravenously, it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. In the event that a patient complains of pain during intended intravenous injection of Mepergan (meperidine and promethazine) , the injection should immediately be stopped to provide for evaluation of possible arterial placement or perivascular extravasation. ASTHMA AND OTHER RESPIRATORY CONDITIONS Meperidine should be used with extreme caution in patients having an acute asthmatic attack, patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve, and patients with preexisting respiratory depression, hypoxia, or hypercapnia. In such patients, even usual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. HYPOTENSIVE EFFECT The administration of meperidine may result in severe hypotension in an individual whose ability to maintain his blood pressure has already been compromised by a depleted blood volume or concurrent administration of drugs such as the phenothiazines or certain anesthetics. USAGE IN AMBULATORY PATIENTS Meperidine 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. Meperidine, like other narcotics, may produce orthostatic hypotension in ambulatory patients. USAGE IN PREGNANCY AND LACTATION Meperidine should not be used in pregnant women prior to the labor period, unless in the judgment of the physician the potential benefits outweigh the possible hazards, because safe use in pregnancy prior to labor has not been established relative to possible adverse effects on fetal development. When used as an obstetrical analgesic, meperidine crosses the placental barrier and can produce respiratory depression in the newborn; resuscitation may be required (see " OVERDOSAGE"). Meperidine appears in the milk of nursing mothers receiving the drug. PRECAUTIONS SUPRAVENTRICULAR TACHYCARDIAS Meperidine should be used with caution in patients with atrial flutter and other supraventricular tachycardias because of a possible vagolytic action which may produce a significant increase in the ventricular response rate. CONVULSIONS Meperidine may aggravate preexisting convulsions in patients with convulsive disorders. If dosage is escalated substantially above recommended levels because of tolerance development, convulsions may occur in individuals without a history of convulsive disorders. ACUTE ABDOMINAL CONDITIONS The administration of meperidine or other narcotics may obscure the diagnosis or clinical course in patients with acute abdominal conditions. SPECIAL-RISK PATIENTS Meperidine should be given with caution, and the initial dose should be reduced in 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. Antiemetics may mask the symptoms of an unrecognized disease and thereby interfere with diagnosis. Patients in pain who have received inadequate or no analgesia have been noted to develop "athetoid-like" movements of the upper extremities following the parenteral administration of promethazine. These symptoms usually disappear upon adequate control of the pain. Ambulatory patients should be cautioned against driving automobiles or operating dangerous machinery until it is known that they do not become drowsy or dizzy from promethazine hydrochloride therapy.