Astramorph pf injection, usp (preservative-free)

Morphine is the most important alkaloid of opium and is a phenanthrene derivative. It is available as the sulfate salt, having the following structural formula:

7,8-Didehydro-4,5-epoxy-17-methyl-(5(alpha),6(alpha))-morphinan-3,6-diol sulfate (2:1) (salt), pentahydrate

(C 17 H 19 NO 3 ) 2 •H 2 SO 4 •5H 2 O Molecular weight is 758.83

Preservative-free ASTRAMORPH/PF (Morphine Sulfate Injection, USP) is a sterile, nonpyrogenic isobaric solution of morphine sulfate free of antioxidants, preservatives or other potentially neurotoxic additives, and is intended for intravenous, epidural or intrathecal administration as a narcotic analgesic. Each milliliter contains morphine sulfate 0.5 mg or 1 mg and sodium chloride 9 mg in Water for Injection. pH range is 2.5-6.5. Ampules and vials are sealed under nitrogen. Each ampule and vial is intended for SINGLE USE ONLY . Discard any unused portion . DO NOT HEAT-STERILIZE.

Astramorph/PF is a systemic narcotic analgesic for administration by the intravenous, epidural or intrathecal routes. It is used for the management of pain not responsive to non-narcotic analgesics. Astramorph/PF, administered epidurally or intrathecally, provides pain relief for extended periods without attendant loss of motor, sensory or sympathetic function.

Astramorph/PF is contraindicated in those medical conditions which would preclude the administration of opioids by the intravenous route--allergy to morphine or other opiates, acute bronchial asthma, upper airway obstruction.

General

Control of pain by neuraxial opiate delivery is always accompanied by considerable risk to the patients and requires a high level of skill to be successfully accomplished. The task of treating these patients must be undertaken by experienced clinical teams, well-versed in patient selection, evolving technology and emerging standards of care. For safety reasons, it is recommended that administration of Astramorph/PF by the epidural or intrathecal routes be limited to the lumbar area. Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use.

Seizures may result from high doses. Patients with known seizure disorders should be carefully observed for evidence of morphine-induced seizure activity.

Use in Patients with Increased Intracranial Pressure or Head Injury

Astramorph/PF should be used with extreme caution in patients with head injury or increased intracranial pressure. Pupillary changes (miosis) from morphine may obscure the existence, extent and course of intracranial pathology. High doses of neuraxial morphine may produce myoclonic events (see WARNINGS and ADVERSE REACTIONS ). Clinicians should maintain a high index of suspicion for adverse drug reactions when evaluating altered mental status or movement abnormalities in patients receiving this modality of treatment.

Use in Chronic Pulmonary Disease

Care is urged in using this drug in patients who have a decreased respiratory reserve (eg., emphysema, severe obesity, kyphoscoliosis or paralysis of the phrenic nerve). Astramorph/PF should not be given in cases of chronic asthma, upper airway obstruction or in any other chronic pulmonary disorder without due consideration of the known risk of acute respiratory failure following morphine administration in such patients.

Use in Hepatic or Renal Disease

The elimination half-life of morphine may be prolonged in patients with reduced metabolic rates and with hepatic and/or renal dysfunction. Hence, care should be exercised in administering Astramorph/PF epidurally to patients with these conditions, since high blood morphine levels, due to reduced clearance, may take several days to develop.

Use in Biliary Surgery or Disorders of the Biliary Tract

As significant morphine is released into the systemic circulation from neuraxial administration, the ensuring smooth muscle hypertonicity may result in biliary colic.

Use with Disorders of the Urinary System

Initiation of neuraxial opiate analgesia is frequently associated with disturbances of micturition, especially in males with prostatic enlargement. Early recognition of difficulty in urination and prompt intervention in cases of urinary retention is indicated.

Use in Ambulatory Patients

Patients with reduced circulating blood volume, impaired myocardial function or on sympatholytic drugs should be monitored for the possible occurrence of orthostatic hypotension, a frequent complication in single-dose neuraxial morphine analgesia.

Use with Other Central Nervous System Depressants

The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics or psychotropic drugs. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Morphine is without known carcinogenic or mutagenic effects and is not known to impair fertility at non-narcotic doses in animals, but studies of the carcinogenic and mutagenic potential or the effect on fertility of Astramorph/PF have not been conducted.

Pregnancy

Teratogenic Effects--Pregnancy Category C.    Morphine sulfate is not teratogenic in rats at 35 mg/kg/day (thirty-five times the usual human dose) but does result in increased pup mortality and growth retardation at doses that narcotize the animal (>10 mg/kg/day, ten times the usual human dose). Astramorph/PF should only be given to pregnant women when no other method of controlling pain is available and means are at hand to manage the delivery and perinatal care of the opiate-dependent infant.

Nonteratogenic Effects.   Infants born to mothers who have been taking morphine chronically may exhibit withdrawal symptoms.

Labor and Delivery

Intravenous morphine readily passes into the fetal circulation and may result in respiratory depression in the neonate. Naloxone and resuscitative equipment should be available for reversal of narcotic-induced respiratory depression in the neonate. In addition, intravenous morphine may reduce the strength, duration and frequency of uterine contraction resulting in prolonged labor.

Epidurally and intrathecally administered morphine readily passes into the fetal circulation and may result in respiratory depression of the neonate. Controlled clinical studies have shown that epidural administration has little or no effect on the relief of labor pain.

Nursing Mothers

Morphine is excreted in maternal milk. Effect on the nursing infant is not known.

Pediatric Use

Adequate studies, to establish the safety and effectiveness of spinal morphine in pediatric patients, have not been performed, and usage in this population is not recommended.

Geriatric Use

The pharmacodynamic effects of neuraxial morphine in the elderly are more variable than in the younger population. Patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects as the dose is increased. Initial doses should be based on careful clinical observation following "test doses", after making due allowances for the effects of the patient's age and infirmity on his/her ability to clear the drug, particularly in patients receiving epidural morphine.

Elderly patients may be more susceptible to respiratory depression and/or respiratory arrest following administration of morphine.

The most serious adverse experience encountered during administration of Astramorph/PF is respiratory depression and/or respiratory arrest. This depression and/or respiratory arrest may be severe and could require intervention (see WARNINGS and OVERDOSAGE ). Because of delay in maximum CNS effect with intravenously administered drug (30 min), rapid administration may result in overdosing. Single-dose neuraxial administration may result in acute or delayed respiratory depression for periods at least as long as 24 hours.

Tolerance and Myoclonus: See WARNINGS for discussion of these and related hazards.

While low doses of intravenously administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulating catecholamines. Excitation of the central nervous system, resulting in convulsions , may accompany high doses of morphine given intravenously. Dysphoric reactions may occur after any size dose and toxic psychoses have been reported.

Pruritus: Single-dose epidural or intrathecal administration is accompanied by a high incidence of pruritus that is dose-related but not confined to the site of administration. Pruritus, following continuous infusion of epidural or intrathecal morphine, is occasionally reported in the literature; these reactions are poorly understood as to their cause.

Urinary Retention: Urinary retention, which may persist 10 to 20 hours following single epidural or intrathecal administration, is a frequent side effect and must be anticipated primarily in male patients, with a somewhat lower incidence in females. Also frequently reported in the literature is the occurrence of urinary retention during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy. Patients who develop urinary retention have responded to cholinomimetic treatment and/or judicious use of catheters (see PRECAUTIONS ).

Constipation: Constipation is frequently encountered during continuous infusion of morphine; this can usually be managed by conventional therapy.

Headache: Lumbar puncture-type headache is encountered in a significant minority of cases for several days following intrathecal catheter implantation; this, generally, responds to bed rest and/or other conventional therapy.

Other: Other adverse experiences reported following morphine therapy include-- Dizziness, euphoria, anxiety, depression of cough reflex, interference with thermal regulation and oliguria . Evidence of histamine release such as urticaria, wheals and/or local tissue irritation may occur. Nausea and vomiting are frequently seen in patients following morphine administration.

Pruritus, nausea/vomiting and urinary retention, if associated with continuous infusion therapy, may respond to intravenous administration of a low dose of naloxone (0.2 mg). The risks of using narcotic antagonists in patients chronically receiving narcotic therapy should be considered.

In general, side effects are amenable to reversal by narcotic antagonists.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Morphine sulfate is a Schedule II narcotic under the United States Controlled Substance Act (21 U.S.C. 801-886).

Morphine is the most commonly cited prototype for narcotic substances that possess an addiction-forming or addiction-sustaining liability. A patient may be at risk for developing a dependence to morphine if used improperly or for overly long periods of time. As with all potent opioids which are µ-agonists, tolerance as well as psychological and physical dependence to morphine may develop irrespective of the route of administration (intravenous, intramuscular, intrathecal, epidural or oral). Individuals with a prior history of opioid or other substance abuse or dependence, being more apt to respond to the euphorogenic and reinforcing properties of morphine, would be considered to be at greater risk.

Care must be taken to avert withdrawal in patients who have been maintained on parenteral/oral narcotics when epidural or intrathecal administration is considered. Withdrawal symptoms may occur when morphine is discontinued abruptly or upon administration of a narcotic antagonist.