Avinza

morphine sulfate

Dosage Form: capsule, extended release
Avinza® C II

(morphine sulfate extended-release capsules)

30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 120 mg


Rx Only

WARNING:

Avinza capsules are a modified-release formulation of morphine sulfate indicated for once daily administration for the relief of moderate to severe pain requiring continuous, around-the-clock opioid therapy for an extended period of time. Avinza CAPSULES ARE TO BE SWALLOWED WHOLE OR THE CONTENTS OF THE CAPSULES SPRINKLED ON APPLESAUCE. THE CAPSULE BEADS ARE NOT TO BE CHEWED, CRUSHED, OR DISSOLVED DUE TO THE RISK OF RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF MORPHINE. PATIENTS MUST NOT CONSUME ALCOHOLIC BEVERAGES WHILE ON Avinza THERAPY. ADDITIONALLY, PATIENTS MUST NOT USE PRESCRIPTION OR NON-PRESCRIPTION MEDICATIONS CONTAINING ALCOHOL WHILE ON Avinza THERAPY. CONSUMPTION OF ALCOHOL WHILE TAKING Avinza MAY RESULT IN THE RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF MORPHINE.

Avinza Description

Avinza (morphine sulfate extended-release capsules) 30, 45, 60, 75, 90, and 120 mg contain both immediate release and extended release beads of morphine sulfate for once daily oral administration.

Chemically, morphine sulfate is 7,8-didehydro-4,5 alpha-epoxy-17-methylmorphinan-3,6 alpha-diol sulfate (2:1) (salt) pentahydrate with a molecular weight of 758. Morphine sulfate occurs as white, feathery, silky crystals; cubical masses of crystal; or white crystalline powder. It is soluble in water and slightly soluble in 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 Avinza Capsule contains either 30, 45, 60, 75, 90, or 120 mg of morphine sulfate, USP and the following inactive ingredients: ammoniomethacrylate copolymers, NF, fumaric acid, NF, povidone, USP, sodium lauryl sulfate, NF, sugar starch spheres, NF, and talc, USP. The capsule shell contains black ink, gelatin, titanium dioxide, D&C yellow No. 10 (30 mg), FD&C blue No. 2 (45 mg), FD&C green No. 3 (60 mg), FDA iron oxide and FDA yellow iron oxide (75 mg), FD&C red No. 40 (90 mg), FD&C red No. 3 (120 mg), and FD&C blue No. 1 (120 mg).

Structure:

Avinza uses the proprietary SODAS® (Spheroidal Oral Drug Absorption System) technology to produce the extended release component of Avinza, which combined with an immediate release component achieves the desired release profile characteristics of Avinza capsules. Within the gastrointestinal tract, due to the permeability of the ammoniomethacrylate copolymers of the beads, fluid enters the beads and solubilizes the drug. This is mediated by fumaric acid, which acts as an osmotic agent and a local pH modifier. The resultant solution then diffuses out in a predetermined manner which prolongs the in vivo dissolution and absorption phases. (see Pharmacokinetics)

Avinza - Clinical Pharmacology

Morphine, a pure opioid agonist, is relatively selective for the mu receptor, although it can interact with other opioid receptors at higher doses. In addition to analgesia, the widely diverse effects of morphine include drowsiness, changes in mood, respiratory depression, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous system.

Effects on the Central Nervous System (CNS): The principal therapeutic action of morphine is analgesia. Other therapeutic effects of morphine include anxiolysis, euphoria and feelings of relaxation. Although the precise mechanism of the analgesic action is unknown, specific CNS opiate receptors and endogenous compounds with morphine-like activity have been identified throughout the brain and spinal cord and are likely to play a role in the expression and perception of analgesic effects. In common with other opioids, morphine causes respiratory depression, in part by a direct effect on the brainstem respiratory centers. Morphine and related opioids depress the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose; however, when asphyxia is present during opioid overdose, marked mydriasis occurs.

Effects on the Gastrointestinal Tract and on Other Smooth Muscle: Gastric, biliary and pancreatic secretions are decreased by morphine. Morphine causes a reduction in motility and is associated with an increase in 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 is increased to the point of spasm. The end result may be constipation. Morphine can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi. Morphine may also cause spasm of the sphincter of the urinary bladder.

Effects on the Cardiovascular System: In therapeutic doses, morphine does not usually exert major effects on the cardiovascular system. Morphine produces peripheral vasodilation which may result in orthostatic hypotension and fainting. Release of histamine can occur, which may play a role in opioid-induced hypotension. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating.

Pharmacodynamics

Morphine concentrations are not predictive of analgesic response, especially in patients previously treated with opioids. The minimum effective concentration varies widely and is influenced by a variety of factors, including the extent of previous opioid use, age, and general medical condition. Effective doses in tolerant patients may be significantly higher than in opioid-naïve patients.

In all patients, the dose of morphine should be titrated on the basis of clinical evaluation of the patient and to achieve a balance between therapeutic and adverse effects.

Pharmacokinetics

Avinza consists of two components, an immediate release component that rapidly achieves plateau morphine plasma concentrations and an extended release component that maintains plasma concentrations throughout the 24-hour dosing interval. The amount of morphine absorbed from Avinza following oral administration is similar to that absorbed from other oral morphine formulations.

The oral bioavailability of morphine is less than 40% and shows large inter-individual variability due to extensive pre-systemic metabolism.

Absorption

Following single-dose oral administration of a 60 mg dose of Avinza under fasting conditions, morphine concentrations of approximately 3 to 6 ng/ml were achieved within 30 minutes after dosing and maintained for the 24-hour dosing interval. The pharmacokinetics of Avinza were shown to be dose-proportional over a single oral dose range of 30 to 120 mg in healthy volunteers and a multiple oral dose range of at least 30 to 180 mg in patients with chronic moderate to severe pain.

Food Effects: When a 60 mg dose of Avinza was administered immediately following a high fat meal, peak morphine concentrations and AUC values were similar to those observed when the dose of Avinza was administered in a fasting state, although achievement of initial concentrations was delayed by approximately 1 hour under fed conditions. Therefore, Avinza can be administered without regard to food. When the contents of Avinza were administered by sprinkling on applesauce, the rate and extent of morphine absorption were found to be bioequivalent to the same dose when administered as an intact capsule.

Steady State: When dosed once-daily, Avinza steady-state pharmacokinetics are characterized by a plateau-like plasma concentration profile. Steady-state plasma concentrations of morphine are achieved 2 to 3 days after initiation of once-daily administration of Avinza.

Avinza 60 mg Capsules (once-daily) and 10 mg morphine oral solution (6 times daily) were equally bioavailable.

A once-daily dose of Avinza provided similar Cmax, Cmin, and AUC values and peak-trough fluctuations (% FL, Cmax-Cmin/Cav) compared to 6-times daily administration of the same total daily dose of morphine oral solution (Table 1).

Table 1 Pharmacokinetic Data Mean ± SD

Parameter	Avinza Capsules Once-Daily	Morphine Oral Solution                       6 - Times Daily
AUC (ng/ml.h)	273.25 ± 81.24	279.11 ± 63.00
Cmax (ng/ml)	18.65 ± 7.13	19.96 ± 4.82
Cmin (ng/ml)	6.98 ± 2.44	6.61 ±2.15
% FL	106.38 ± 78.14	116.22 ±26.67

Distribution

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Although the primary site of action is the CNS, only small quantities cross the blood-brain barrier. Morphine also crosses the placental membranes and has been found in breast milk. The volume of distribution of morphine is approximately 1 to 6 L/kg, and morphine is 20 to 35% reversibly bound to plasma proteins.

Metabolism

The major pathway of morphine detoxification is conjugation, either with D-glucuronic acid to produce glucuronides or with sulfuric acid to produce morphine-3-etheral sulfate. While a small fraction (less than 5%) of morphine is demethylated, virtually all morphine is converted by hepatic metabolism to the 3- and 6-glucuronide metabolites (M3G and M6G; about 50% and 15%, respectively). M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.

Excretion

Most of a dose of morphine is excreted in urine as M3G and M6G, with elimination of morphine occurring primarily as renal excretion of M3G. Approximately 10% of the dose is excreted unchanged in urine. A small amount of the glucuronide conjugates are excreted in bile, with minor enterohepatic recycling. Seven to 10% of administered morphine is excreted in the feces.

The mean adult plasma clearance is approximately 20 to 30 ml/min/kg. The effective terminal half-life of morphine after IV administration is reported to be approximately 2 hours. In some studies involving longer periods of plasma sampling, a longer terminal half-life of morphine of about 15 hours was reported.

In Vitro Avinza-Alcohol Interaction

In vitro studies performed by the FDA demonstrated that when Avinza 30 mg was mixed with 900 mL of buffer solutions containing ethanol (20% and 40%), the dose of morphine that was released was alcohol concentration-dependent, leading to a more rapid release of morphine. While the relevance of in vitro lab tests regarding Avinza to the clinical setting remains to be determined, this acceleration of release may correlate with in vivo rapid release of the total morphine dose, which could result in the absorption of a potentially fatal dose of morphine.

Special Populations

Geriatric: Elderly patients (aged 65 years or older) may have increased sensitivity to morphine. Avinza pharmacokinetics have not been studied specifically in elderly patients. 

Nursing Mothers: Low levels of morphine sulfate have been detected in maternal milk. The milk:plasma morphine AUC ratio is about 2.5:1. The amount of morphine delivered to the infant depends on the plasma concentration of the mother, the amount of milk ingested by the infant, and the extent of first-pass metabolism.

Pediatric: The pharmacokinetics of Avinza have not been studied in pediatric patients below the age of 18. The range of dose strengths available may not be appropriate for treatment of very young pediatric patients. Sprinkling on applesauce is NOT a suitable alternative for these patients.

Gender: A gender analysis of pharmacokinetic data from healthy subjects taking Avinza indicated that morphine concentrations were similar in males and females.

Race: There may be some pharmacokinetic differences associated with race. In one published study, Chinese subjects given intravenous morphine had a higher clearance when compared to Caucasian subjects (1852 +/- 116 ml/min compared to 1495 +/- 80 ml/min).

Hepatic Failure: Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis. Clearance was found to decrease with a corresponding increase in half-life. The M3G and M6G to morphine plasma AUC ratios also decreased in these subjects, indicating diminished metabolic activity.

Renal Insufficiency: Morphine pharmacokinetics are altered in patients with renal failure. Clearance is decreased and the metabolites, M3G and M6G, may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function.

Drug-Drug Interactions: Known drug-drug interactions involving morphine are pharmacodynamic, not pharmacokinetic. (see PRECAUTIONS, Drug Interactions)

Clinical Studies

Avinza was studied in over 140 healthy volunteers and 560 patients with chronic, moderate to severe pain who participated in 6 pharmacokinetic studies, 4 clinical studies and 3 studies which provided both pharmacokinetic and clinical data. The patient population included those who were either receiving chronic opioid therapy or had a prior sub-optimal response to acetaminophen and/or NSAID therapy, as well as patients who previously received intermittent opioid analgesic therapy. In the controlled clinical studies, patients were followed from 7 days to up to 4 weeks, and in the open label studies, patients were followed for up to 6 to 12 months.

Avinza was studied in a double-blind, placebo-controlled, fixed-dose, parallel group trial in 295 patients with moderate to severe pain due to osteoarthritis. These patients had either a prior sub-optimal response to acetaminophen, NSAID therapy, or previously received intermittent opioid analgesic therapy. Thirty-milligrams Avinza capsules administered once-daily, either in the morning or the evening, were more effective than placebo in reducing pain.

Table 2 Change from Baseline in WOMAC OA Index Pain VAS Subscale Score

* P<0.05; REPEATED MEASURES ANALYSIS
Overall	Placebo	Avinza QAM	Avinza QPM
LS Mean	-36.23	-75.26*	-75.39*
Std. Error	11.482	11.305	11.747

This study was not designed to assess the effects of Avinza on the course of the osteoarthritis.

Indications and Usage for Avinza

Avinza capsules are a modified-release formulation of morphine sulfate intended for once daily administration indicated for the relief of moderate to severe pain requiring continuous, around-the-clock opioid therapy for an extended period of time.

Avinza is NOT intended for use as a prn analgesic.

The safety and efficacy of using Avinza in the postoperative setting has not been evaluated. Avinza is not indicated for postoperative use. If the patient has been receiving the drug prior to surgery, resumption of the pre-surgical dose may be appropriate once the patient is able to take the drug by mouth. Physicians should individualize treatment, moving from parenteral to oral analgesics as appropriate. (see American Pain Society guidelines)

Contraindications

Avinza is contraindicated in patients with known hypersensitivity to morphine, morphine salts, or any components of the product. Avinza, like all opioids, is contraindicated in patients with respiratory depression in the absence of resuscitative equipment and in patients with acute or severe bronchial asthma.

Avinza, like all opioids, is contraindicated in any patient who has or is suspected of having paralytic ileus.

Warnings

Avinza must be swallowed whole (not chewed, crushed, or dissolved) or Avinza may be opened and the entire bead contents sprinkled on a small amount of applesauce immediately prior to ingestion. THE CAPSULES MUST NOT BE CHEWED, CRUSHED, OR DISSOLVED DUE TO THE RISK OF RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF MORPHINE. (see BOX WARNING, CLINICAL PHARMACOLOGY)

Patients must not consume alcoholic beverages while on Avinza therapy. Additionally, patients must not use prescription or non-prescription medications containing alcohol while on Avinza therapy. Consumption of alcohol while taking Avinza may result in the rapid release and absorption of a potentially fatal dose of morphine.

THE DAILY DOSE OF Avinza MUST BE LIMITED TO A MAXIMUM OF 1600 MG/DAY. Avinza DOSES OF OVER 1600 MG/DAY CONTAIN A QUANTITY OF FUMARIC ACID THAT HAS NOT BEEN DEMONSTRATED TO BE SAFE, AND WHICH MAY RESULT IN SERIOUS RENAL TOXICITY.

Misuse, Abuse and Diversion of Opioids

Morphine is an opioid agonist and a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty.

Morphine can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Avinza in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Abuse of Avinza by crushing, chewing, snorting, or injecting the dissolved product will result in the immediate release of the entire daily dose of the opioid and pose a significant risk to the abuser that could result in overdose and death. Intravenous abuse of a water extract of Avinza may lead to serious pulmonary complications due to the extraction of talc along with morphine sulfate. (see DRUG ABUSE AND ADDICTION)

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Interactions with Alcohol and Drugs of Abuse

Morphine may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. In vitro studies performed by the FDA demonstrated that when Avinza 30 mg was mixed with 900 mL of buffer solutions containing ethanol (20% and 40%), the dose of morphine that was released was alcohol concentration-dependent, leading to a more rapid release of morphine. While the relevance of in vitro lab tests regarding Avinza to the clinical setting remains to be determined, this acceleration of release may correlate with in vivo rapid release of the total morphine dose, which could result in the absorption of a potentially fatal dose of morphine.

Impaired Respiration

Respiratory depression is the chief hazard of all morphine preparations. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation.

Morphine should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale and in patients having a substantially decreased respiratory reserve (e.g., severe kyphoscoliosis), hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of morphine may increase airway resistance and decrease respiratory drive to the point of apnea.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of morphine with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Morphine produces effects which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries. Morphine should only be administered under such circumstances when considered essential and then with extreme care.

Hypotensive Effect

Avinza, like all morphine products, may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by a depleted blood volume or concurrent administration of drugs such as phenothiazines or general anesthetics. (see also PRECAUTIONS, Drug Interactions) Avinza may produce orthostatic hypotension and syncope in ambulatory patients.

Avinza is an opioid analgesic which should be administered with caution to patients in circulatory shock, as vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Gastrointestinal Obstruction

Avinza should not be administered to patients with gastrointestinal obstruction, especially paralytic ileus because Avinza, like all morphine preparations, diminishes propulsive peristaltic waves in the gastrointestinal tract and may prolong the obstruction.

Precautions

General

Avinza is intended for use in patients requiring continuous around-the-clock treatment with an opioid analgesic. It is not appropriate as a prn treatment for pain. As with any opioid, it is critical to adjust the dose of Avinza for each individual patient, taking into account the patient’s prior experience with analgesics. (see DOSAGE AND ADMINISTRATION)

Use in Pancreatic/Biliary Tract Disease

Avinza should be used with caution in patients with biliary tract disease, including acute pancreatitis, as morphine may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions.

Special Risk Groups

Avinza should be administered cautiously and in reduced dosages in patients with severe renal or hepatic insufficiency, Addison's disease, hypothyroidism, prostatic hypertrophy, or urethral stricture, and in elderly or debilitated patients. (see Geriatric Use and CLINICAL PHARMACOLOGY, Special Populations)

Caution should be exercised in the administration of morphine to patients with CNS depression, toxic psychosis, acute alcoholism and delirium tremens, and seizure disorders.

Driving and Operating Machinery

Patients should be cautioned that Avinza could impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

Patients should also be cautioned about the potential combined effects of Avinza with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics and alcohol. (see PRECAUTIONS, Drug Interactions)

Tolerance and Physical Dependence

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). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other 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.

In general, opioids should not be abruptly discontinued. (see DOSAGE AND ADMINISTRATION, Cessation of Therapy)

Information for Patients

Patients receiving Avinza (morphine sulfate extended-release capsules) should be given the following instructions by the physician:

1. Patients should be advised that Avinza capsules contain morphine and should be taken once daily.


2. Avinza must be swallowed whole (not chewed, crushed, or dissolved) or Avinza may be opened and the entire bead contents sprinkled on a small amount of applesauce immediately prior to ingestion. The beads must NOT be chewed, crushed, or dissolved due to the risk of exposure to a potentially toxic dose of morphine.


3. Patients should be informed that they must not consume alcoholic beverages while on Avinza therapy. Additionally, patients should be informed that they must not use prescription or non-prescription medication containing alcohol while on Avinza therapy. Consumption of alcohol while taking Avinza may result in the rapid release and absorption of a potentially fatal dose of morphine.


4. The dose of Avinza should not be adjusted without consulting with a physician or other healthcare professional.


5. Patients should be advised that Avinza may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients started on Avinza or patients whose dose has been adjusted should refrain from any potentially dangerous activity until it is established that they are not adversely affected.


6. Patients should be advised that Avinza should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers). A physician should be consulted if other medications are currently being used or are added in the future.


7. Women of childbearing potential who become or are planning to become pregnant should consult a physician prior to initiating or continuing therapy with Avinza.


8. If patients have been receiving treatment with Avinza for more than a few weeks and cessation of therapy is indicated, they should be counseled on the importance of safely tapering the dose and that abruptly discontinuing the medication could precipitate withdrawal symptoms. The physician should provide a dose schedule to accomplish a gradual discontinuation of the medication.


9. Patients should be advised that Avinza is a potential drug of abuse. They should protect it from theft. It should never be given to anyone other than the individual for whom it was prescribed.


10. Patients should be instructed to keep Avinza in a secure place out of the reach of children. When Avinza is no longer needed, the unused capsules should be destroyed by flushing down the toilet.

As with other opioids, patients taking Avinza should be advised of the potential for severe constipation; appropriate laxatives, and/or stool softeners as well as other appropriate treatments should be initiated from the onset of opioid therapy.

Drug Interactions

CNS Depressants: The concurrent use of other central nervous system (CNS) depressants including sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, or other tranquilizers or alcohol increases the risk of respiratory depression, hypotension, profound sedation, or coma. Use with caution and in reduced dosages in patients taking these agents.

Muscle Relaxants: Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Mixed Agonist/Antagonist Opioid Analgesics: Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine and butorphanol) should NOT be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

Monoamine Oxidase Inhibitors (MAOIs): MAOIs markedly potentiate the action of morphine. Avinza should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

Cimetidine: Concomitant administration of morphine and cimetidine has been reported to precipitate apnea, confusion and muscle twitching in an isolated report. Patients should be monitored for increased respiratory and CNS depression when receiving cimetidine concomitantly with Avinza.

Food: Avinza can be administered without regard to food. (see CLINICAL PHARMACOLOGY, Food Effects).

Carcinogenicity/Mutagenicity/Impairment of Fertility

Studies in animals to evaluate the carcinogenic potential of morphine sulfate have not been conducted. No formal studies to assess the mutagenic potential of morphine have been conducted. In the published literature, the results of in vitro studies showed  that morphine is non-mutagenic in the Drosophila melanogaster lethal mutation assay and produced no evidence of chromosomal aberrations when incubated with murine splenocytes. Contrary to these results, morphine was found to increase DNA fragmentation when incubated in vitro with a human lymphoma cell line. In vivo, morphine has been reported to produce an increase in the frequency of micronuclei in bone marrow cells and immature red blood cells in the mouse micronucleus test and to induce chromosomal aberrations in murine lymphocytes and spermatids. Some of the in vivo clastogenic effects reported with morphine in mice may be directly related to increases in glucocorticoid levels produced by morphine in this species.

Pregnancy

Teratogenic Effects (Pregnancy Category C)

No formal studies to assess the teratogenic effects of morphine in animals have been performed. Several literature reports indicate that morphine administered subcutaneously during the early gestational period in mice and hamsters produced neurological, soft tissue and skeletal abnormalities. With one exception, the effects that have been reported were following doses that were maternally toxic and the abnormalities noted were characteristic of those observed when maternal toxicity is present. In one study, following subcutaneous infusion of doses greater than or equal to 0.15 mg/kg to mice, exencephaly, hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed sternebrae, and malformed xiphoid were noted in the absence of maternal toxicity. In the hamster, morphine sulfate given subcutaneously on gestation day 8 produced exencephaly and cranioschisis. Morphine was not a significant teratogen in the rat at exposure levels significantly beyond that normally encountered in clinical practice. In one study however, decreased litter size and viability were observed in the offspring of male rats administered morphine at doses approximately 3-fold the maximum recommended human daily dose (MRHDD) for 10 days prior to mating. In two studies performed in the rabbit, no evidence of teratogenicity was reported at subcutaneous doses up to 100 mg/kg.

In humans, the frequency of congenital anomalies has been reported to be no greater than expected among the children of 70 women who were treated with morphine during the first four months of pregnancy or in 448 women treated with this drug anytime during pregnancy. Furthermore, no malformations were observed in the infant of a woman who attempted suicide by taking an overdose of morphine and other medication during the first trimester of pregnancy.

Nonteratogenic Effects

Published literature has reported that exposure to morphine during pregnancy is associated with reduction in growth and a host of behavioral abnormalities in the offspring of animals. Morphine treatment during gestational periods of organogenesis in rats, hamsters, guinea pigs and rabbits resulted in the following treatment-related embryotoxicity and neonatal toxicity in one or more studies: decreased litter size, embryo-fetal viability, fetal and neonatal body weights, absolute brain and cerebellar weights, lengths or widths at birth and during the neonatal period, delayed motor and sexual maturation, and increased neonatal mortality, cyanosis and hypothermia. Decreased fertility in female offspring, and decreased plasma and testicular levels of luteinizing hormone and testosterone, decreased testes weights, seminiferous tubule shrinkage, germinal cell aplasia, and decreased spermatogenesis in male offspring were also observed. Behavioral abnormalities resulting from chronic morphine exposure of fetal animals included altered reflex and motor skill development, mild withdrawal, and altered responsiveness to morphine persisting into adulthood.

Controlled studies of chronic in utero morphine exposure in pregnant women have not been conducted. Infants born to mothers who have taken opioids chronically may exhibit withdrawal symptoms, reversible reduction in brain volume, small size, decreased ventilatory response to CO2 and increased risk of sudden infant death syndrome. Morphine sulfate should be used by a pregnant woman only if the need for opioid analgesia clearly outweighs the potential risks to the fetus.

Labor and Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Avinza is not recommended for use in women during and immediately prior to labor, when use of shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression. A specific opioid antagonist, such as naloxone or nalmefene, should be available for reversal of opioid-induced respiratory depression in the neonate.

Neonatal Withdrawal Syndrome

Chronic maternal use of opioids during pregnancy may cause newborns to suffer from neonatal withdrawal syndrome (NWS) following birth. Manifestations of this syndrome include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The time and amount of the mother’s last dose, and the rate of elimination of the drug from the newborn may affect the onset, duration, and severity of the disorder. When severe symptoms occur, pharmacologic intervention may be required.

Nursing Mothers

Low levels of morphine sulfate have been detected in human milk. Breast-feeding infants might experience withdrawal symptoms upon cessation of Avinza administration to the mother. Because of the potential for nursing infants to experience adverse reactions, a decision should be made whether to discontinue nursing or discontinue Avinza, taking into account the benefit of the drug to the mother.

Pediatric Use

Safety and effectiveness of Avinza in pediatric patients below the age of 18 have not been established. The range of dose strengths available may not be appropriate for treatment of very young pediatric patients. Sprinkling on applesauce is NOT a suitable alternative for these patients.

Geriatric Use

Of the total number of subjects in clinical studies of Avinza, there were 168 patients age 65 and over, including 64 patients over the age of 74, 100 of whom were treated with Avinza. Subgroup analyses comparing efficacy were not possible given the small number of subjects in each treatment group. No overall differences in safety were observed between these subjects and younger subjects. In general, caution should be exercised in the selection of the starting dose of Avinza for an elderly patient, usually starting at the low end of the dosing range. As with all opioids, the starting dose should be reduced in debilitated and non-tolerant patients. (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric, and PRECAUTIONS, Special Risk Groups)

Adverse Reactions

In controlled and open label clinical studies, 560 patients with chronic malignant or non-malignant pain were treated with Avinza. The most common serious adverse events reported with administration of Avinza were vomiting, nausea, death, dehydration, dyspnea, and sepsis. (Deaths occurred in patients treated for pain due to underlying malignancy.) Serious adverse events caused by morphine include respiratory depression, apnea, and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.

Adverse Events

The common adverse events seen on initiation of therapy with morphine are dose-dependent and are typical opioid-related side effects. The most frequent of these include constipation, nausea and somnolence. The frequency of these events depends upon several factors including the clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual. These events should be anticipated and managed as part of opioid analgesia therapy.

The most common adverse events (seen in greater than 10%) reported by patients treated with Avinza during the clinical trials at least once during therapy were constipation, nausea, somnolence, vomiting, and headache. Adverse events occurring in 5-10% of study patients were peripheral edema, diarrhea, abdominal pain, infection, urinary tract infection, accidental injury, flu syndrome, back pain, rash, sweating, fever, insomnia, depression, paresthesia, anorexia, dry mouth, asthenia and dyspnea. Other less common side effects expected from opioid analgesics, including morphine, or seen in fewer than 5% of patients taking Avinza in the clinical trials were:

Body as a Whole: malaise, withdrawal syndrome.

Cardiovascular System: bradycardia, hypertension, hypotension, palpitations, syncope, tachycardia.

Digestive System: biliary pain, dyspepsia, dysphagia, gastroenteritis, abnormal liver function tests, rectal disorder, thirst.

Hemic and Lymphatic System: anemia, thrombocytopenia.

Metabolic and Nutritional Disorders: edema, weight loss.

Musculoskeletal: skeletal muscle rigidity.

Nervous System: abnormal dreams, abnormal gait, agitation, amnesia, anxiety, ataxia, confusion, convulsions, coma, delirium, euphoria, hallucinations, lethargy, nervousness, abnormal thinking, tremor, vasodilation, vertigo.

Respiratory System: hiccup, hypoventilation, voice alteration.

Skin and Appendages: dry skin, urticaria.

Special Senses: amblyopia, eye pain, taste perversion.

Urogenital System: abnormal ejaculation, dysuria, impotence, decreased libido, oliguria, urinary retention.

DRUG ABUSE AND ADDICTION

Avinza is a mu-agonist opioid and is a Schedule II controlled substance. Morphine, like other opioids used in analgesia, can be abused and is subject to criminal diversion.

Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.

“Drug-seeking” behavior is very common in addicts and drug abusers. 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 physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence. The converse is also true. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests 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.

Avinza is intended for oral use only. Abuse of the crushed capsule poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol and other substances. With parenteral abuse, the capsule excipients, especially talc, can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Avinza OVERDOSAGE

Symptoms

Acute overdosage with morphine is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, and death.

Treatment

Primary attention should be given to re-establishment of a patent airway and institution of assisted or controlled ventilation when overdose of an extended-release formulation such as Avinza has been ingested. Elimination or evacuation of gastric contents may be necessary in order to eliminate unabsorbed drug. Before attempting treatment by gastric emptying or activated charcoal, care should be taken to secure the airway. Pure opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. Since the duration of reversal is expected to be less than the duration of action of Avinza, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Avinza, as with other controlled delivery preparations in overdose situations, may continue to release morphine for 36 to 48 hours or longer following ingestion, and management of an overdose should be monitored accordingly. If the response to opioid antagonists is suboptimal or only brief in nature, additional antagonist should be administered as directed by the manufacturer of the product.

Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdose. Such agents should be administered cautiously to persons who are known, or suspected to be physically dependent on Avinza. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome.

Opioid-Tolerant Individuals: In an individual physically dependent on opioids, administration of the usual dose of the antagonist wi

K-Phos Neutral

Pronunciation: poe-TAS-ee-um and SOE-dee-um FOS-fates
Generic Name: Potassium and Sodium Phosphates
Brand Name: Examples include K-Phos Neutral and Phospha 250 Neutral

K-Phos Neutral is used for:

Increasing phosphate levels in the urine. It may also be used for other conditions as determined by your doctor.

K-Phos Neutral is a phosphorus supplement. It works by providing phosphate to the body.

Do NOT use K-Phos Neutral if:

• you are allergic to any ingredient in K-Phos Neutral


• you have severe kidney problems, infected kidney stones, or impacted feces


• you have decreased urination or are unable to urinate


• you have high levels of phosphate or potassium in the blood

Contact your doctor or health care provider right away if any of these apply to you.

Before using K-Phos Neutral:

Some medical conditions may interact with K-Phos Neutral. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have high blood sodium levels, low blood calcium levels, or you are on a sodium-restricted or potassium-restricted diet


• if you have a history of heart problems (eg, heart failure), kidney problems, kidney or other urinary stones, certain muscle problems (eg, myotonia congenita, rhabdomyolysis), stomach or bowel problems (eg, inflammation), liver problems, adrenal gland problems (eg, Addison disease), inflammation of the pancreas, or parathyroid problems


• if you have preeclampsia (high blood pressure during pregnancy)


• if you are dehydrated or have rickets, softened or weakened bones, or a urinary tract infection


• if you have a condition in which your skin is breaking down (eg, severe burns)

Some MEDICINES MAY INTERACT with K-Phos Neutral. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Aldosterone blockers (eg, eplerenone), aliskiren, angiotensin-converting enzyme (ACE) inhibitors (eg, enalapril), potassium-sparing diuretics (eg, triamterene), or potassium supplements because high potassium levels, possibly with irregular heartbeat or a heart attack, may occur


• Corticosteroids (eg, prednisone, corticotropin) or medicine for high blood pressure (eg, diazoxide, guanethidine, hydralazine, methyldopa) because the risk of high blood sodium levels may be increased


• Digoxin because the risk of its side effects may be increased by K-Phos Neutral

This may not be a complete list of all interactions that may occur. Ask your health care provider if K-Phos Neutral may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use K-Phos Neutral:

Use K-Phos Neutral as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take K-Phos Neutral by mouth with meals and at bedtime, unless your doctor tells you otherwise.


• Take K-Phos Neutral with a full glass of water (8 oz/240 mL).


• Do not take antacids containing aluminum, magnesium, or calcium with K-Phos Neutral without checking with your doctor or pharmacist.


• If you miss a dose of K-Phos Neutral, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use K-Phos Neutral.

Important safety information:

• K-Phos Neutral may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use K-Phos Neutral with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• While taking K-Phos Neutral, the possibility of passing old kidney stones is increased.


• Check with your doctor before you use a salt substitute or a product that has potassium in it.


• Lab tests, including kidney function and electrolyte levels (eg, calcium, potassium, phosphorus, sodium), may be performed while you use K-Phos Neutral. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• K-Phos Neutral should be used with extreme caution in CHILDREN younger than 4 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: It is not known if K-Phos Neutral can cause harm to the fetus. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using K-Phos Neutral while you are pregnant. It is not known if K-Phos Neutral is found in breast milk. If you are or will be breast-feeding while you use K-Phos Neutral, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of K-Phos Neutral:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; nausea; stomach pain; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bone or joint pain; confusion; decreased urination; dizziness; increased thirst; irregular heartbeat; muscle cramps; numbness or tingling around the lips; numbness, tingling, pain, or weakness in the hands or feet; seizures; severe or persistent diarrhea; shortness of breath; swelling of the hands, ankles, or feet; unusual tiredness; unusual weakness or heaviness of the legs; unusual weight gain.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: K-Phos Neutral side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of K-Phos Neutral:

Store K-Phos Neutral at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep K-Phos Neutral out of the reach of children and away from pets.

General information:

• If you have any questions about K-Phos Neutral, please talk with your doctor, pharmacist, or other health care provider.


• K-Phos Neutral is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about K-Phos Neutral. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More K-Phos Neutral resources

• K-Phos Neutral Side Effects (in more detail)
• K-Phos Neutral Use in Pregnancy & Breastfeeding
• Drug Images
• K-Phos Neutral Drug Interactions
• K-Phos Neutral Support Group
• 0 Reviews for K-Phos Neutral - Add your own review/rating

• K-Phos Neutral Concise Consumer Information (Cerner Multum)


• K-Phos Neutral Advanced Consumer (Micromedex) - Includes Dosage Information

Compare K-Phos Neutral with other medications

• Hypophosphatemia
• Urinary Acidification

Flolan

epoprostenol sodium

Dosage Form: injection, powder, lyophilized, for solution
Flolan®

(epoprostenol sodium)

for Injection

Flolan Description

Flolan (epoprostenol sodium) for Injection is a sterile sodium salt formulated for intravenous (IV) administration. Each vial of Flolan contains epoprostenol sodium equivalent to either 0.5 mg (500,000 ng) or 1.5 mg (1,500,000 ng) epoprostenol, 3.76 mg glycine, 2.93 mg sodium chloride, and 50 mg mannitol. Sodium hydroxide may have been added to adjust pH.

Epoprostenol (PGI2, PGX, prostacyclin), a metabolite of arachidonic acid, is a naturally occurring prostaglandin with potent vasodilatory activity and inhibitory activity of platelet aggregation.

Epoprostenol is (5Z,9α,11α,13E,15S)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid.

Epoprostenol sodium has a molecular weight of 374.45 and a molecular formula of C20H31NaO5. The structural formula is:

Flolan is a white to off-white powder that must be reconstituted with STERILE DILUENT for Flolan. STERILE DILUENT for Flolan is supplied in glass vials containing 50 mL of 94 mg glycine, 73.3 mg sodium chloride, sodium hydroxide (added to adjust pH), and Water for Injection, USP.

The reconstituted solution of Flolan has a pH of 10.2 to 10.8 and is increasingly unstable at a lower pH.

Flolan - Clinical Pharmacology

General

Epoprostenol has 2 major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right- and left-ventricular afterload and increase cardiac output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose. At low doses, there is vagally mediated bradycardia, but at higher doses, epoprostenol causes reflex tachycardia in response to direct vasodilation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacologic effects of epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying.

Pharmacokinetics

Epoprostenol is rapidly hydrolyzed at neutral pH in blood and is also subject to enzymatic degradation. Animal studies using tritium-labeled epoprostenol have indicated a high clearance (93 mL/kg/min), small volume of distribution (357 mL/kg), and a short half-life (2.7 minutes). During infusions in animals, steady-state plasma concentrations of tritium-labeled epoprostenol were reached within 15 minutes and were proportional to infusion rates.

No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol. The in vitro half-life of epoprostenol in human blood at 37°C and pH 7.4 is approximately 6 minutes; therefore, the in vivo half-life of epoprostenol in humans is expected to be no greater than 6 minutes. The in vitro pharmacologic half-life of epoprostenol in human plasma, based on inhibition of platelet aggregation, was similar for males (n = 954) and females (n = 1,024).

Tritium-labeled epoprostenol has been administered to humans in order to identify the metabolic products of epoprostenol. Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. The recovery of radioactivity in urine and feces over a 1-week period was 82% and 4% of the administered dose, respectively. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans.

CLINICAL TRIALS IN PULMONARY ARTERIAL HYPERTENSION (PAH)

Acute Hemodynamic Effects

Acute intravenous infusions of Flolan for up to 15 minutes in patients with idiopathic or heritable PAH or PAH associated with scleroderma spectrum of diseases (PAH/SSD) produce dose-related increases in cardiac index (CI) and stroke volume (SV) and dose-related decreases in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR), and mean systemic arterial pressure (SAPm). The effects of Flolan on mean pulmonary artery pressure (PAPm) were variable and minor.

Chronic Infusion in Idiopathic or Heritable PAH

Hemodynamic Effects

 Chronic continuous infusions of Flolan in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomized trials of 8 and 12 weeks’ duration comparing Flolan plus conventional therapy to conventional therapy alone. Dosage of Flolan was determined as described in DOSAGE AND ADMINISTRATION and averaged 9.2 ng/kg/min at study’s end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one half to two thirds of patients; and supplemental oxygen in about half the patients. Except for 2 New York Heart Association (NYHA) functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 studies, the pooled results are described. Chronic hemodynamic effects were generally similar to acute effects. Increases in CI, SV, and arterial oxygen saturation and decreases in PAPm, mean right atrial pressure (RAPm), TPR, and systemic vascular resistance (SVR) were observed in patients who received Flolan chronically compared to those who did not. Table 1 illustrates the treatment-related hemodynamic changes in these patients after 8 or 12 weeks of treatment.

Table 1. Hemodynamics During Chronic Administration of Flolan in Patients With Idiopathic or Heritable PAH

	Baseline		Mean Change from Baseline at End of Treatment Period*
Hemodynamic Parameter	Flolan (N = 52)	Standard Therapy (N = 54)	Flolan (N = 48)	Standard Therapy (N = 41)
CI (L/min/m2)	2.0	2.0	0.3†	-0.1
PAPm (mm Hg)	60	60	-5†	1
PVR (Wood U)	16	17	-4†	1
SAPm (mm Hg)	89	91	-4	-3
SV (mL/beat)	44	43	6†	-1
TPR (Wood U)	20	21	-5†	1

* At 8 weeks: Flolan N = 10, conventional therapy N = 11 (N is the number of patients with hemodynamic data).

At 12 weeks: Flolan N = 38, conventional therapy N = 30 (N is the number of patients with hemodynamic data).

† Denotes statistically significant difference between Flolan and conventional therapy groups.

CI = cardiac index, PAPm = mean pulmonary arterial pressure, PVR = pulmonary vascular resistance, SAPm = mean systemic arterial pressure, SV = stroke volume, TPR = total pulmonary resistance.

These hemodynamic improvements appeared to persist when Flolan was administered for at least 36 months in an open, nonrandomized study.

Clinical Effects

Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk test in patients receiving continuous intravenous Flolan plus conventional therapy (N = 52) for 8 or 12 weeks compared to those receiving conventional therapy alone (N = 54). Improvements were apparent as early as the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvement in dyspnea and fatigue, as measured by the Chronic Heart Failure Questionnaire and the Dyspnea Fatigue Index.

Survival was improved in NYHA functional Class III and Class IV patients with idiopathic or heritable PAH treated with Flolan for 12 weeks in a multicenter, open, randomized, parallel study. At the end of the treatment period, 8 of 40 (20%) patients receiving conventional therapy alone died, whereas none of the 41 patients receiving Flolan died (p = 0.003).

Chronic Infusion in PAH/Scleroderma Spectrum of Diseases (SSD)

Hemodynamic Effects

Chronic continuous infusions of Flolan in patients with PAH/SSD were studied in a prospective, open, randomized trial of 12 weeks’ duration comparing Flolan plus conventional therapy (N = 56) to conventional therapy alone (N = 55). Except for 5 NYHA functional Class II patients, all patients were either functional Class III or Class IV. Dosage of Flolan was determined as described in DOSAGE AND ADMINISTRATION and averaged 11.2 ng/kg/min at study’s end. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients, supplemental oxygen and diuretics in two thirds of the patients, oral vasodilators in 40% of the patients, and digoxin in a third of the patients. A statistically significant increase in CI, and statistically significant decreases in PAPm, RAPm, PVR, and SAPm after 12 weeks of treatment were observed in patients who received Flolan chronically compared to those who did not. Table 2 illustrates the treatment-related hemodynamic changes in these patients after 12 weeks of treatment.

Table 2. Hemodynamics During Chronic Administration of Flolan in Patients With PAH/SSD

	Baseline		Mean Change from Baseline at 12 Weeks
Hemodynamic Parameter	Flolan (N = 56)	Conventional Therapy (N = 55)	Flolan (N = 50)	Conventional Therapy (N = 48)
CI (L/min/m2)	1.9	2.2	0.5*	-0.1
PAPm (mm Hg)	51	49	-5*	1
RAPm (mm Hg)	13	11	-1*	1
PVR (Wood U)	14	11	-5*	1
SAPm (mm Hg)	93	89	-8*	-1

* Denotes statistically significant difference between Flolan and conventional therapy groups (N is the number of patients with hemodynamic data).

CI = cardiac index, PAPm = mean pulmonary arterial pressure, RAPm = mean right arterial pressure, PVR = pulmonary vascular resistance, SAPm = mean systemic arterial pressure.

Clinical Effects

Statistically significant improvement was observed in exercise capacity, as measured by the 6-minute walk, in patients receiving continuous intravenous Flolan plus conventional therapy for 12 weeks compared to those receiving conventional therapy alone. Improvements were apparent in some patients at the end of the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnea and fatigue, as measured by the Borg Dyspnea Index and Dyspnea Fatigue Index. At week 12, NYHA functional class improved in 21 of 51 (41%) patients treated with Flolan compared to none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%] with Flolan and 35/48 [73%] with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with Flolan and 13/48 (27%) with conventional therapy alone worsened. Of the patients randomized, NYHA functional class data at 12 weeks were not available for 5 patients treated with Flolan and 7 patients treated with conventional therapy alone.

No statistical difference in survival over 12 weeks was observed in PAH/SSD patients treated with Flolan as compared to those receiving conventional therapy alone. At the end of the treatment period, 4 of 56 (7%) patients receiving Flolan died, whereas 5 of 55 (9%) patients receiving conventional therapy alone died.

No controlled clinical trials with Flolan have been performed in patients with pulmonary hypertension associated with other diseases.

Indications and Usage for Flolan

Flolan is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases.

Contraindications

A large study evaluating the effect of Flolan on survival in NYHA Class III and IV patients with congestive heart failure due to severe left ventricular systolic dysfunction was terminated after an interim analysis of 471 patients revealed a higher mortality in patients receiving Flolan plus conventional therapy than in those receiving conventional therapy alone. The chronic use of Flolan in patients with congestive heart failure due to severe left ventricular systolic dysfunction is therefore contraindicated.

Some patients with pulmonary hypertension have developed pulmonary edema during dose initiation, which may be associated with pulmonary veno-occlusive disease. Flolan should not be used chronically in patients who develop pulmonary edema during dose initiation.

Flolan is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.

Warnings

Flolan must be reconstituted only as directed using STERILE DILUENT for Flolan. Flolan must not be reconstituted or mixed with any other parenteral medications or solutions prior to or during administration.

Abrupt Withdrawal

Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of Flolan may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. In clinical trials, one Class III patient's death was judged attributable to the interruption of Flolan. Avoid abrupt withdrawal.

Sepsis

See ADVERSE REACTIONS: Adverse Events Attributable to the Drug Delivery System.

Precautions

General

Flolan should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension. Carefully establish the diagnosis of idiopathic or heritable PAH or PAH/CTD.

Flolan is a potent pulmonary and systemic vasodilator. Initiate Flolan in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. Dose initiation has been performed during right heart catheterization and without cardiac catheterization. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.

Flolan is a potent inhibitor of platelet aggregation. Therefore, expect an increased risk for hemorrhagic complications, particularly for patients with other risk factors for bleeding (see PRECAUTIONS: Drug Interactions).

During chronic use, deliver Flolan continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving Flolan to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. To reduce the risk of infection, use aseptic technique in the reconstitution and administration of Flolan and in routine catheter care. Because Flolan is metabolized rapidly, even brief interruptions in the delivery of Flolan may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. Intravenous therapy with Flolan will likely be needed for prolonged periods, possibly years, so consider the patient's ability to accept and care for a permanent intravenous catheter and infusion pump.

Based on clinical trials, the acute hemodynamic response to Flolan did not correlate well with improvement in exercise tolerance or survival during chronic use of Flolan. Adjust dosage of Flolan during chronic use at the first sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated with Flolan (see DOSAGE AND ADMINISTRATION).  Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours.

Information for Patients

Patients receiving Flolan should receive the following information. Flolan must be reconstituted only with STERILE DILUENT for Flolan. Flolan is infused continuously through a permanent indwelling central venous catheter via a small, portable infusion pump. Thus, therapy with Flolan requires commitment by the patient to drug reconstitution, drug administration, and care of the permanent central venous catheter. Patients must adhere to sterile technique in preparing the drug and in the care of the catheter, and even brief interruptions in the delivery of Flolan may result in rapid symptomatic deterioration. A patient’s decision to receive Flolan should be based upon the understanding that there is a high likelihood that therapy with Flolan will be needed for prolonged periods, possibly years. The patient's ability to accept and care for a permanent intravenous catheter and infusion pump should also be carefully considered.

Drug Interactions

Additional reductions in blood pressure may occur when Flolan is administered with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet agents or anticoagulants are used concomitantly, there is the potential for Flolan to increase the risk of bleeding. However, patients receiving infusions of Flolan in clinical trials were maintained on anticoagulants without evidence of increased bleeding. In clinical trials, Flolan was used with digoxin, diuretics, anticoagulants, oral vasodilators, and supplemental oxygen.

In a pharmacokinetic substudy in patients with congestive heart failure receiving furosemide or digoxin in whom therapy with Flolan was initiated, apparent oral clearance values for furosemide (n = 23) and digoxin (n = 30) were decreased by 13% and 15%, respectively, on the second day of therapy and had returned to baseline values by day 87. The change in furosemide clearance value is not likely to be clinically significant. However, patients on digoxin may show elevations of digoxin concentrations after initiation of therapy with Flolan, which may be clinically significant in patients prone to digoxin toxicity.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. A micronucleus test in rats revealed no evidence of mutagenicity. The Ames test and DNA elution tests were also negative, although the instability of epoprostenol makes the significance of these tests uncertain. Fertility was not impaired in rats given Flolan by subcutaneous injection at doses up to 100 mcg/kg/day (600 mcg/m2/day, 2.5 times the recommended human dose [4.6 ng/kg/min or 245.1 mcg/m2/day, IV] based on body surface area).

Pregnancy

Pregnancy Category B. Reproductive studies have been performed in pregnant rats and rabbits at doses up to 100 mcg/kg/day (600 mcg/m2/day in rats, 2.5 times the recommended human dose, and 1,180 mcg/m2/day in rabbits, 4.8 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to Flolan. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

The use of Flolan during labor, vaginal delivery, or cesarean section has not been adequately studied in humans.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Flolan is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Flolan in pulmonary hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Adverse Reactions

During clinical trials, adverse events were classified as follows: (1) adverse events during dose initiation and escalation, (2) adverse events during chronic dosing, and (3) adverse events associated with the drug delivery system.

Adverse Events During Dose Initiation and Escalation

During early clinical trials, Flolan was increased in 2-ng/kg/min increments until the patients developed symptomatic intolerance. The most common adverse events and the adverse events that limited further increases in dose were generally related to vasodilation, the major pharmacologic effect of Flolan. The most common dose-limiting adverse events (occurring in ≥1% of patients) were nausea, vomiting, headache, hypotension, and flushing, but also include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia. Table 3 lists the adverse events reported during dose initiation and escalation in decreasing order of frequency.

Table 3. Adverse Events During Dose Initiation and Escalation

Adverse Events Occurring in ≥1% of Patients	Flolan (n = 391)
Flushing	58%
Headache	49%
Nausea/vomiting	32%
Hypotension	16%
Anxiety, nervousness, agitation	11%
Chest pain	11%
Dizziness	8%
Bradycardia	5%
Abdominal pain	5%
Musculoskeletal pain	3%
Dyspnea	2%
Back pain	2%
Sweating	1%
Dyspepsia	1%
Hypesthesia/paresthesia	1%
Tachycardia	1%

Adverse Events During Chronic Administration

Interpretation of adverse events is complicated by the clinical features of PAH, which are similar to some of the pharmacologic effects of Flolan (e.g., dizziness, syncope). Adverse events which may be related to the underlying disease include dyspnea, fatigue, chest pain, edema, hypoxia, right ventricular failure, and pallor. Several adverse events, on the other hand, can clearly be attributed to Flolan. These include hypotension, bradycardia, tachycardia, pulmonary edema, bleeding at various sites, thrombocytopenia, headache, abdominal pain, pain (unspecified), sweating, rash, arthralgia, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, anxiety/nervousness, and agitation. In addition, chest pain, fatigue, and pallor have been reported during Flolan therapy, and a role for the drug in these events cannot be excluded.

Adverse Events During Chronic Administration for Idiopathic or Heritable PAH

In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 4 lists adverse events that occurred at a rate at least 10% greater on Flolan in controlled trials.

Table 4. Adverse Events Regardless of Attribution Occurring in Patients With Idiopathic or Heritable PAH With ≥10% Difference Between Flolan and Conventional Therapy Alone

Adverse Event	Flolan (n = 52)	Conventional Therapy (n = 54)
Occurrence More Common With Flolan
General
Chills/fever/sepsis/flu-like symptoms	25%	11%
Cardiovascular
Tachycardia	35%	24%
Flushing	42%	2%
Gastrointestinal
Diarrhea	37%	6%
Nausea/vomiting	67%	48%
Musculoskeletal
Jaw pain	54%	0%
Myalgia	44%	31%
Nonspecific musculoskeletal pain	35%	15%
Neurological
Anxiety/nervousness/tremor	21%	9%
Dizziness	83%	70%
Headache	83%	33%
Hypesthesia, hyperesthesia, paresthesia	12%	2%

Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving Flolan.

Adverse Events During Chronic Administration for PAH/SSD

In an effort to separate the adverse effects of the drug from the adverse effects of the underlying disease, Table 5 lists adverse events that occurred at a rate at least 10% greater on Flolan in the controlled trial.

Table 5. Adverse Events Regardless of Attribution Occurring in Patients with PAH/SSD With ≥10% Difference Between Flolan and Conventional Therapy Alone

Adverse Event	Flolan (n = 56)	Conventional Therapy (n = 55)
Occurrence More Common With Flolan
Cardiovascular
Flushing	23%	0%
Hypotension	13%	0%
Gastrointestinal
Anorexia	66%	47%
Nausea/vomiting	41%	16%
Diarrhea	50%	5%
Musculoskeletal
Jaw pain	75%	0%
Pain/neck pain/arthralgia	84%	65%
Neurological
Headache	46%	5%
Skin and Appendages
Skin ulcer	39%	24%
Eczema/rash/urticaria	25%	4%

Although the relationship to Flolan administration has not been established, pulmonary embolism has been reported in several patients taking Flolan and there have been reports of hepatic failure.

Adverse Events Attributable to the Drug Delivery System

Chronic infusions of Flolan are delivered using a small, portable infusion pump through an indwelling central venous catheter. During controlled PAH trials of up to 12 weeks’ duration, the local infection rate was about 18%, and the rate for pain was about 11%. During long-term follow-up, sepsis was reported at a rate of 0.3 infections/patient per year in patients treated with Flolan. This rate was higher than reported in patients using chronic indwelling central venous catheters to administer parenteral nutrition, but lower than reported in oncology patients using these catheters. Malfunctions in the delivery system resulting in an inadvertent bolus of or a reduction in Flolan were associated with symptoms related to excess or insufficient Flolan, respectively (see ADVERSE REACTIONS: Adverse Events During Chronic Administration).

Observed During Clinical Practice

In addition to adverse reactions reported from clinical trials, the following events have been identified during post-approval use of Flolan. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Flolan.

Blood and Lymphatic

Anemia, hypersplenism, pancytopenia, splenomegaly.

Endocrine and Metabolic

Hyperthyroidism.

Overdosage

Signs and symptoms of excessive doses of Flolan during clinical trials are the expected dose-limiting pharmacologic effects of Flolan, including flushing, headache, hypotension, tachycardia, nausea, vomiting, and diarrhea. Treatment will ordinarily require dose reduction of Flolan.

One patient with PAH/CTD accidentally received 50 mL of an unspecified concentration of Flolan. The patient vomited and became unconscious with an initially unrecordable blood pressure. Flolan was discontinued and the patient regained consciousness within seconds. In clinical practice, fatal occurrences of hypoxemia, hypotension, and respiratory arrest have been reported following overdosage of Flolan.

Single intravenous doses of Flolan at 10 and 50 mg/kg (2,703 and 27,027 times the recommended acute phase human dose based on body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity were hypoactivity, ataxia, loss of righting reflex, deep slow breathing, and hypothermia.

Flolan Dosage and Administration

Important Note

Flolan must be reconstituted only with STERILE DILUENT for Flolan. Do not dilute reconstituted solutions of Flolan or administer with other parenteral solutions or medications (see WARNINGS).

Dosage

Administer continuous chronic infusion of Flolan through a central venous catheter. Temporary peripheral intravenous infusion may be used until central access is established. Initiate chronic infusion of Flolan at 2 ng/kg/min and increase in increments of 2 ng/kg/min every 15 minutes or longer until dose-limiting pharmacologic effects are elicited or until a tolerance limit to the drug is established or further increases in the infusion rate are not clinically warranted (see Dosage Adjustments). If dose-limiting pharmacologic effects occur, then decrease the infusion rate until Flolan is tolerated. In clinical trials, the most common dose-limiting adverse events were nausea, vomiting, hypotension, sepsis, headache, abdominal pain, or respiratory disorder (most treatment-limiting adverse events were not serious). If the initial infusion rate of 2 ng/kg/min is not tolerated, identify a lower dose that is tolerated by the patient.

In the controlled 12-week trial in PAH/SSD, for example, the dose increased from a mean starting dose of 2.2 ng/kg/min. During the first 7 days of treatment, the dose was increased daily to a mean dose of 4.1 ng/kg/min on day 7 of treatment. At the end of week 12, the mean dose was 11.2 ng/kg/min. The mean incremental increase was 2 to 3 ng/kg/min every 3 weeks.

Dosage Adjustments

Base changes in the chronic infusion rate on persistence, recurrence, or worsening of the patient's symptoms of pulmonary hypertension and the occurrence of adverse events due to excessive doses of Flolan. In general, expect increases in dose from the initial chronic dose.

Consider increments in dose if symptoms of PAH persist or recur Increase the infusion by 1- to 2-ng/kg/min increments at intervals sufficient to allow assessment of clinical response; these intervals should be at least 15 minutes. In clinical trials, incremental increases in dose occurred at intervals of 24 to 48 hours or longer. Following establishment of a new chronic infusion rate, observe the patient, and monitor standing and supine blood pressure and heart rate for several hours to ensure that the new dose is tolerated.

During chronic infusion, the occurrence of dose-limiting pharmacological events may necessitate a decrease in infusion rate, but the adverse event may occasionally resolve without dosage adjustment. Make dosage decreases gradually in 2-ng/kg/min decrements every 15 minutes or longer until the dose-limiting effects resolve. Avoid abrupt withdrawal of Flolan or sudden large reductions in infusion rates. Except in life-threatening situations (e.g., unconsciousness, collapse, etc.), adjust infusion rates of Flolan only under the direction of a physician.

In patients receiving lung transplants, doses of Flolan were tapered after the initiation of cardiopulmonary bypass.

Administration

Flolan is administered by continuous intravenous infusion via a central venous catheter using an ambulatory infusion pump. During initiation of treatment, Flolan may be administered peripherally.

The ambulatory infusion pump used to administer Flolan should: (1) be small and lightweight, (2) be able to adjust infusion rates in 2-ng/kg/min increments, (3) have occlusion, end-of-infusion, and low-battery alarms, (4) be accurate to ±6% of the programmed rate, and (5) be positive pressure-driven (continuous or pulsatile) with intervals between pulses not exceeding 3 minutes at infusion rates used to deliver Flolan. The reservoir should be made of polyvinyl chloride, polypropylene, or glass. The infusion pump used in the most recent clinical trials was the CADD-1 HFX 5100 (SIMS Deltec). A 60-inch microbore non-DEHP extension set with proximal antisyphon valve, low priming volume (0.9 mL), and in-line 0.22 micron filter was used during clinical trials.

To avoid interruptions in drug delivery, the patient should have access to a backup infusion pump and intravenous infusion sets. Consider a multi-lumen catheter if other intravenous therapies are routinely administered.

To facilitate extended use at ambient temperatures exceeding 25°C (77°F), a cold pouch with frozen gel packs was used in clinical trials (see DOSAGE AND ADMINISTRATION: Storage