Astramorph PF

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• slow, shallow, or irregular breathing
• sleepiness
• loss of consciousness
• cold, clammy skin
• small pupils
• slow heartbeat
• blurred vision
• nausea
• fainting

In the U.S.

• Astramorph PF
• Duramorph
• Infumorph

Available Dosage Forms:

• Solution
• Injectable

Therapeutic Class: Analgesic

Chemical Class: Opioid

It is very important that your doctor check the progress or you or your child while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to use it.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that can make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers, or sleeping medicine; other prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before you or your child take any of the medicines listed above while you are using this medicine.

This medicine may be habit-forming. If you or your child feel that the medicine is not working as well, do not use more than your prescribed dose. Call your doctor for instructions.

Using narcotics for a long time can cause severe constipation. To prevent this, your doctor may direct you or your child to take laxatives, drink a lot of fluids, or increase the amount of fiber in the diet. Be sure to follow the directions carefully, because continuing constipation can lead to more serious problems.

Dizziness, lightheadedness, or fainting may occur when you or your child get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve the dizziness or lightheadedness.

This medicine may make you dizzy, drowsy, confused, or disoriented. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you or your child are using this medicine. Serious unwanted effects can occur if certain medicines are given together with morphine injection.

If you or your child have been using this medicine regularly for several weeks or longer, do not suddenly stop using it without checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent worsening of your condition and reduce the possibility of withdrawal symptoms, such as abdominal or stomach cramps, anxiety, fever, nausea, runny nose, sweating, tremors, or trouble with sleeping.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Difficult or troubled breathing
• irregular, fast or slow, or shallow breathing
• pale or blue lips, fingernails, or skin
• shortness of breath
• very slow breathing

• Blurred vision
• convulsions
• decrease in frequency of urination
• decrease in the amount of urine
• difficulty in passing urine (dribbling)
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• painful urination
• sweating
• unusual tiredness or weakness

Get emergency help immediately if any of the following symptoms of overdose occur:

• Bluish lips or skin
• dizziness
• fainting
• irregular heartbeat
• lightheadedness
• low blood pressure or pulse
• slow heartbeat
• unconsciousness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Absent, missed, or irregular menstrual periods
• anxiety
• confusion
• decreased interest in sexual intercourse
• delusions
• depersonalization
• difficulty having a bowel movement (stool)
• false or unusual sense of well-being
• hallucinations
• headache
• inability to have or keep an erection
• itching skin
• loss in sexual ability, desire, drive, or performance
• menstrual changes
• nausea and vomiting
• stopping of menstrual bleeding

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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-(5α,6α)-morphinan-3,6-diol sulfate (2:1) (salt), pentahydrate

        (C17H19NO3)2 •H2SO4 • 5H2O                                              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.

Morphine produces a wide spectrum of pharmacologic effects including analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility and physical dependence.  Opiate analgesia involves at least three anatomical areas of the central nervous system: the periaqueductal-periventricular gray matter, the ventromedial medulla and the spinal cord.  A systemically administered opiate may produce analgesia by acting at any, all or some combination of these distinct regions.  Morphine interacts predominantly with the μ-receptor.  The μ-binding sites of opioids are very discretely distributed in the human brain, with high densities of sites found in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen and certain cortical areas.  They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve.

Morphine has an apparent volume of distribution ranging from 1.0 to 4.7 L/kg after intravenous dosage.  Protein binding is low, about 36%, and muscle tissue binding is reported as 54%.  A blood-brain barrier exists, and when morphine is introduced outside of the CNS (e.g., intravenously), plasma concentrations of morphine remain higher than the corresponding CSF morphine levels.  Conversely, when morphine is injected into the intrathecal space, it diffuses out into the systemic circulation slowly, accounting for the long duration of action of morphine administered by this route.

Morphine has a total plasma clearance which ranges from 0.9 to 1.2 L/kg/h (liters/kilogram/hour) in postoperative patients, but shows considerable interindividual variation.  The major pathway of clearance is hepatic glucuronidation to morphine-3-glucuronide, which is pharmacologically inactive.  The major excretion path of the conjugate is through the kidneys, with about 10% in the feces.  Morphine is also eliminated by the kidneys, 2 to 12% being excreted unchanged in the urine. Terminal half-life is commonly reported to vary from 1.5 to 4.5 hours, although the longer half-lives were obtained when morphine levels were monitored over protracted periods with very sensitive radioimmunoassay methods.  The accepted elimination half-life in normal subject is 1.5 to 2 hours.

"Selective" blockade of pain sensation is possible by neuraxial application of morphine.  In addition, duration of analgesia may be much longer by this route compared to systemic administration.  However, CNS effects, associated with systemic administration, are still seen.  These include respiratory depression, sedation, nausea and vomiting, pruritus and urinary retention.  In particular, both early and late respiratory depression (up to 24 hours post dosing) have been reported following neuraxial administration.  Circulation of the spinal fluid may also result in high concentrations of morphine reaching the brain stem directly.

The incidence of unwanted CNS effects, including delayed respiratory depression, associated with neuraxial application of morphine, is related to the circulatory dynamics of the epidural venous plexus and the spinal fluid.  The lipid solubility and degree of ionization of morphine plays an important part in both the onset and duration of analgesia and the CNS effects. Morphine has a pKa 7.9, with an octanol/water partition coefficient of 1.42 at pH 7.4.  At this pH, the tertiary amino group in each of the opioids is mostly ionized, making the molecule water soluble.  Morphine, with additional hydroxyl groups on the molecule, is significantly more water soluble than any other opioid in clinical use.

Morphine, injected into the epidural space, is rapidly absorbed into the general circulation.  Absorption is so rapid that the plasma concentration-time profiles closely resemble those obtained after intravenous or intramuscular administration.  Peak plasma concentrations averaging 33 to 40 ng/mL (range 5 to 62 ng/mL) are achieved within 10 to 15 minutes after administration of 3 mg of morphine.  Plasma concentrations decline in a multiexponential fashion.  The terminal half-life is reported to range from 39 to 249 minutes (mean of 90±34.3 min) and, though somewhat shorter, is similar in magnitude as values reported after intravenous and intramuscular administration (1.5 to 4.5 h).  CSF concentrations of morphine, after epidural doses of 2 to 6 mg in postoperative patients, have been reported to be 50 to 250 times higher than corresponding plasma concentrations.  The CSF levels of morphine exceed those in plasma after only 15 minutes and are detectable for as long as 20 hours after the injection of 2 mg of epidural morphine.  Approximately 4% of the dose injected epidurally reaches the CSF.  This corresponds to the relative minimum effective epidural and intrathecal doses of 5 mg and 0.25 mg, respectively.  The disposition of morphine in the CSF follows a biphasic pattern, with an early half-life of 1.5 h and a late phase half-life of about 6 h.  Morphine crosses the dura slowly, with an absorption half-life across the dura averaging 22 minutes.  Maximum CSF concentrations are seen 60 to 90 minutes after injection.  Minimum effective CSF concentrations for postoperative analgesia average 150 ng/mL (range <1 to 380 ng/mL).

The intrathecal route of administration circumvents meningeal diffusion barriers and, therefore, lower doses of morphine produce comparable analgesia to that induced by the epidural route.  After intrathecal bolus injection of morphine, there is a rapid initial distribution phase lasting 15 to 30 minutes and a half-life in the CSF of 42 to 136 min (mean 90 ± 16 min). Derived from limited data, it appears that the disposition of morphine in the CSF, from 15 minutes postintrathecal administration to the end of a six-hour observation period, represents a combination of the distribution and elimination phases.  Morphine concentrations in the CSF averaged 332 ± 137 ng/mL at 6 hours, following a bolus dose of 0.3 mg of morphine.  The apparent volume of distribution of morphine in the intrathecal space is about 22 ± 8 mL.

Time-to-peak plasma concentrations, however, are similar (5 to 10 min) after either epidural or intrathecal bolus administration of morphine.  Maximum plasma morphine concentrations after 0.3 mg intrathecal morphine have been reported from <1 to 7.8 ng/mL.  The minimum analgesic morphine plasma concentration during Patient-Controlled Analgesia (PCA) has been reported as 20 to 40 ng/mL, suggesting that any analgesic contribution from systemic redistribution would be minimal after the first 30 to 60 minutes with epidural administration and virtually absent with intrathecal administration of morphine.

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  WARNINGSand 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 (e.g., 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 ensuing 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:

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. 

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.  Effects on the nursing infant are 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.

PARENTERAL ADMINISTRATION OF NARCOTICS IN PATIENTS RECEIVING EPIDURAL OR INTRATHECAL MORPHINE MAY RESULT IN OVERDOSAGE.

Overdosage of morphine is characterized by respiratory depression, with or without concomitant CNS depression.  In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur.  Since respiratory arrest may result either through direct depression of the respiratory center or as the result of hypoxia, primary attention should be given to the establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted, or controlled, ventilation.  The narcotic antagonist, naloxone, is a specific antidote.  An initial dose of 0.4 to 2 mg of naloxone should be administered intravenously, simultaneously with respiratory resuscitation.  If the desired degree of counteraction and improvement in respiratory function is not obtained, naloxone may be repeated at 2- to 3-minute intervals.  If no response is observed after 10 mg of naloxone has been administered, the diagnosis of narcotic-induced, or partial narcotic-induced, toxicity should be questioned.  Intramuscular or subcutaneous administration may be used if the intravenous route is not available.

As the duration of effect of naloxone is considerably shorter than that of epidural or intrathecal morphine, repeated administration may be necessary.  Patients should be closely observed for evidence of renarcotization.

Preservative-Free ASTRAMORPH/PFTM (Morphine Sulfate Injection, USP) is available in ampules and single dose vials for intravenous, epidural, or intrathecal administration:

Storage

PROTECT FROM LIGHT. Store in carton at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature] until ready to use.  DO NOT FREEZE.

Astramorph/PF contains no preservative or antioxidant.  DISCARD ANY UNUSED PORTION.  DO NOT HEAT-STERILIZE.

All trademarks are the property of APP Pharmaceuticals, LLC.

Manufactured for:

451103/Revised: June 2008

PACKAGE LABEL- PRINCIPAL DISPLAY- Astramorph 2 mL Ampule Carton Panel

NDC 63323-291-80

279180

10 Ampules, 2 mL

Astramorph/PF™
(Morphine Sulfate Injection, USP)

1 mg/2 mL (0.5 mg/mL)

For IV, Epidural, or Intrathecal Administration.

Preservative-Free

Rx only

PACKAGE LABEL- PRINCIPAL DISPLAY- Astramorph 2 mL Ampule Label

NDC 63323-291-80

2 mL

Astramorph/PF™
(Morphine Sulfate Injection, USP)

1 mg/2 mL (0.5 mg/mL)

Preservative-Free

PACKAGE LABEL- PRINCIPAL DISPLAY- Astramorph 10 mL Ampule Carton Panel

NDC 63323-291-97

279197

Astramorph/PF™
(Morphine Sulfate Injection, USP)

5 mg/10 mL (0.5 mg/mL)

For IV, Epidural, or Intrathecal Administration.

Preservative-Free

Rx only

Contains Five 10 mL Ampules

PACKAGE LABEL- PRINCIPAL DISPLAY- Astramorph 10 mL Ampule Label

NDC 63323-291-97

10 mL

Preservative-Free

Astramorph/PF™
(Morphine Sulfate Injection, USP)

5 mg/10 mL (0.5 mg/mL)

For IV, Epidural, or Intrathecal Administration.

PACKAGE LABEL- PRINCIPAL DISPLAY- Astramorph 10 mL Single Use Vial Carton Panel

NDC 63323-292-10

279210

Contains Five 10 mL Single Use Vials
E-Z OFF™ vial
Preservative-Free

Astramorph/PF™
(Morphine Sulfate Injection, USP)

10 mg/10 mL (1 mg/mL)

For IV, Epidural, or Intrathecal Administration.

Rx only

PACKAGE LABEL- PRINCIPAL DISPLAY- Astramorph 10 mL Single Use Vial Label

NDC 63323-292-10

279210

Astramorph/PF™
(Morphine Sulfate Injection, USP)

10 mg/10 mL (1 mg/mL)

For IV, Epidural, or Intrathecal Administration.

10 mL Single Use Vial