Infumorph

Unless your doctor tells you otherwise, continue your normal diet.

Infumorph is part of the drug class:

• Natural opium alkaloids

Tell your doctor about all the medications you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• anticoagulants ('blood thinners') such as warfarin (Coumadin, Jantoven)
• antidepressants such as amitriptyline (Elavil), amoxapine (Asendin), clomipramine (Anafranil), desipramine (Norpramin), doxepin (Adapin, Sinequan), imipramine (Tofranil), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil)
• antihistamines (found in cold and allergy medications)
• beta blockers such as atenolol (Tenormin), labetalol (Normodyne), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), and propranolol (Inderal)
• buprenorphine (Butrans, Subutex, in Suboxone)
• butorphanol (Stadol)
• cimetidine (Tagamet)
• diuretics ('water pills')
• medications for anxiety, seizures, depression, mental illness, or nausea
• monoamine oxidase (MAO) inhibitors, including isocarboxazid (Marplan), phenelzine (Nardil), procarbazine (Matulane), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate)
• muscle relaxants
• nalbuphine (Nubain)
• other narcotic pain medications
• pentazocine (Talwin)
• quinidine  
• sedatives, sleeping pills, or tranquilizers

This is not a complete list of Infumorph drug interactions. Ask your doctor or pharmacist for more information.

Infumorph may be habit-forming. There is a greater risk that you will overuse Infumorph if you have or have ever had depression or another mental illness, or if you have abused alcohol, used street drugs, or overused prescription medications.

Infumorph may cause slowed or stopped breathing, especially when you begin your treatment and any time your dose is increased. Tell your doctor if you have slowed breathing and if you have or have ever had lung disease such as asthma, chronic obstructive pulmonary disease (COPD; a group of diseases including chronic bronchitis and emphysema that cause difficulty breathing), or other breathing problems. If you experience any of the following symptoms, call your doctor immediately or get emergency medical treatment: slowed breathing, long pauses between breaths, or shortness of breath.

Taking certain other medications during your treatment with Infumorph may increase the risk that you will experience breathing problems or other serious, life-threatening side effects.

Do not receive Infumorph if you have:

• severe asthma, trouble breathing, or other lung problems.
• a bowel blockage or have narrowing of the stomach or intestines.

While receiving Infumorph do not:

• Drive or operate heavy machinery, until you know how Infumorph affects you. Infumorph can make you sleepy, dizzy, or lightheaded.
• Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.

In the U.S.

• Astramorph PF
• Duramorph
• Infumorph

Available Dosage Forms:

• Solution
• Injectable

Therapeutic Class: Analgesic

Chemical Class: Opioid

Infumorph is for use in continuous microinfusion devices and indicated only for intrathecal or epidural infusion in the management of intractable chronic pain severe enough to require an opioid analgesic and for which less invasive means of controlling pain are inadequate.

Limitations of Use

Not for single-dose intravenous, intramuscular, or subcutaneous administration due to the risk of overdose.

Not for single-dose neuraxial injection because Infumorph is too concentrated for accurate delivery of the smaller doses used in this setting.

Table 1 includes clinically significant drug interactions with Infumorph.

Table 1. Clinically Significant Drug Interactions with Infumorph

Controlled Substance

Infumorph contains morphine, a Schedule II controlled drug substance.

Abuse

Infumorph contains morphine, a substance with a high potential for abuse similar to other opioids. Infumorph can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.3)].

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Infumorph, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors).  Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug.  Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Infumorph should not be abruptly discontinued [see Dosage and Administration (2.6)].  If Infumorph is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Infumorph (preservative-free morphine sulfate sterile solution) is an opioid agonist, available as a sterile, nonpyrogenic, isobaric, high potency solution of morphine sulfate in strengths of 10 mg or 25 mg morphine sulfate per mL, free of antioxidants, preservatives or other potentially neurotoxic additives. Infumorph is intended for use in continuous microinfusion devices for intraspinal administration in the management of pain. Morphine is the most important alkaloid of opium and is a phenanthrene derivative. It is available as the sulfate salt, chemically identified as 7,8-Didehydro-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3,6-diol sulfate (2:1) (salt), pentahydrate, with the following structural formula:

 (C17H19NO3)2 • H2SO4 • 5H2O                                         Molecular Weight is 758.83

Morphine sulfate USP is an odorless, white crystalline powder with a bitter taste. It has a solubility of 1 in 21 parts of water and 1 in 1000 parts of alcohol,, but is practically insoluble in chloroform or ether. The octanol:water partition coefficient of morphine is 1.42 at physiologic pH and the pKa is 7.9 for the tertiary nitrogen (the majority is ionized at pH 7.4).

Each mL of Infumorph 200 contains morphine sulfate, USP 10 mg (200 mg/20 mL) and sodium chloride 8 mg in Water for Injection, USP. Each mL of Infumorph 500 contains morphine sulfate, USP 25 mg (500 mg/20 mL) and sodium chloride 6.25 mg in Water for Injection, USP. If needed, sodium hydroxide and/or sulfuric acid are added for pH adjustment to 4.5. Contains no preservative. Each 20 mL ampul of Infumorph is intended for SINGLE USE ONLY.

Mechanism of Action

Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

Pharmacodynamics

Effects on the Central Nervous System

Morphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

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.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Morphine produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritis, flushing, red eyes and sweating and/or orthostatic hypotension.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and lutenizing hormone (LH) in humans [See Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6)]. 

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration – Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [See Dosage and Administration (2.1)].

Concentration – Adverse Reaction Relationships

There is a relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [See Dosage and Administration (2.1, 2.2, 2.6)].

Pharmacokinetics

Epidural Administration

Absorption

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 33–40 ng/mL (range 5–62 ng/mL) are achieved within 10 to 15 minutes after administration of 3 mg of morphine.

Distribution

Plasma concentrations decline in a multiexponential fashion. 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 60–90 minutes after injection. Minimum effective CSF concentrations for postoperative analgesia average 150 ng/mL (range < 1‑380 ng/mL).

Elimination

The terminal half-life is reported to range from 39 to 249 minutes (mean of 90 ± 34.3 min) for epidural administration.

Metabolism

The major pathway of clearance is hepatic glucuronidation to morphine-3-glucuronide, which is pharmacologically inactive.

Excretion

The major excretion path of the morphine-3-glucuronide 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.

Intrathecal Administration

Absorption

Time-to-peak plasma concentrations, however, are similar (5-10 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 20–40 ng/mL, suggesting that any analgesic contribution from systemic redistribution would be minimal after the first 30–60 minutes with epidural administration and virtually absent with intrathecal administration of morphine.

Distribution

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 15–30 minutes and a half-life in the CSF of 42–136 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.