on :

Drug Name: Legal Class: CD

VICTANYL

Drug Class: Opiates How Fentanyl Supplied: 25 microgram/hr, 5=25.89. 50 microgram/hr, 5=48.36. 75 microgram/hr, 5=67.41. Price: 100 microgram/hr, 5=83.09. Transparent and colourless transdermal patches with blue imprint on the backing foil and marked with name and strength. Indications: Severe chronic pain. Opioid-naive patients: Initially, patch with release rate of 12.5 microgram/hr. Opioid-tolerant patients: Apply strength of patch according to previous analgesics. See SPC. Adults: Apply patch to non-hairy area of chest or upper arm, remove and replace with new patch every 72 hrs using a different site. Titrate in 12.5 or 25 microgram/hr increments until pain controlled. Consider other analgesics if dose exceeds 300 microgram/hr. Under 2 years, not recommended. 216 years, opioid tolerant patients only: apply strength of patch according to previous analgesics. See SPC. Children: In young children, apply patch to upper back to minimise potential for removal and monitor adhesion. Remove and replace with new patch every 72 hrs using a different site. Titrate in 12 microgram/hr increments until pain controlled. General Warnings for Fentanyl Severe respiratory depression, severe obstructive lung conditions, severe Contraindications: CNS impairment, bradycardia. Lactation. Fencino, Mezolar Matrix: soya/peanut allergy. Instanyl: previous facial radiotherapy, recurrent epistaxis. COPD, raised intracranial pressure, impaired consciousness, head injury, brain tumour, renal or hepatic impairment, hypovolaemia, hypotension. Monitor for signs of respiratory depression. Myasthenia gravis. Risk of tolerance and dependence (esp in patients with history of drug or alcohol Precautions: dependence); withdraw gradually. Elderly or debilitated patients. Opioid-naive patients. Pregnancy. Dispose of patches and oral units with care. Patches: fever, avoid exposure of application site to direct heat. Do not cut patches. Avoid touching adhesive side, wash hands after use. Abstral: mouth wounds or mucositis. MAOIs, SSRIs, SNRIs, other serotonergic drugs, CNS depressants, Interactions: inducers or inhibitors of CYP3A4, grapefruit juice, buprenorphine, pentazocine. Instanyl, PecFent: other intranasal drugs. Hypotension, hypertension, somnolence, sedation, dizziness, Side Effects:

General Warnings for Fentanyl hallucinations, pruritus, sweating, bradycardia, tachycardia, palpitations, GI upset, urinary retention, headache, confusion, asthenia, fatigue, dyspnoea, respiratory depression, anxiety, anorexia, insomnia, depression, tremor, paraesthesia, muscle spasm, oedema. Oral use: mouth ulceration, dry mouth, flushing. Nasal spray: epistaxis, rhinorrhoea, nasal discomfort, flushing, hot flushes, throat irritation, dysgeusia. Patches: application site reactions. Additional Notes: Effentora, PecFent: Report any adverse reaction to CHM.

Section: Pain Sub Section: Pain, fever (View Prescribing Notes) Drug Class: Opiates Manufacturer: Zentiva Drug Name: Legal Class: CD

OSMANIL

Drug Class: Opiates How Fentanyl Supplied: 12 microgram/hr (releases 12.5 microgram/hr), 5=18.11. 25 microgram/hr, 5=26.94. 50 microgram/hr, 5=50.32. Price: 75 microgram/hr, 5=70.15. 100 microgram/hr, 5=86.46. Transparent and colourless transdermal patches with blue imprint on the backing foil and marked with name and strength. Indications: Severe chronic pain which can be adequately managed only with opioid analgesics. Opioid-naive patients: Initially 12.5 microgram/hr. Opioid-tolerant patients: Apply strength of patch according to previous analgesics. See SPC. Adults: Apply patch to non-hairy area of chest or upper arm, remove and replace with new patch every 72 hrs using a different site. Titrate in 12.5 or 25 microgram/hr increments until pain controlled. Consider other analgesics if dose exceeds 300 microgram/hr. 216 years; opioid-tolerant patients only, receiving at least 30mg oral Children: morphine equivalents per day: Apply strength of patch according to previous analgesics. See SPC. Apply patch to upper back. General Warnings for Fentanyl Contraindications: Severe respiratory depression, severe obstructive lung conditions, severe CNS impairment, bradycardia. Lactation.

Precautions:

Interactions:

Side Effects:

General Warnings for Fentanyl Fencino, Mezolar Matrix: soya/peanut allergy. Instanyl: previous facial radiotherapy, recurrent epistaxis. COPD, raised intracranial pressure, impaired consciousness, head injury, brain tumour, renal or hepatic impairment, hypovolaemia, hypotension. Monitor for signs of respiratory depression. Myasthenia gravis. Risk of tolerance and dependence (esp in patients with history of drug or alcohol dependence); withdraw gradually. Elderly or debilitated patients. Opioid-naive patients. Pregnancy. Dispose of patches and oral units with care. Patches: fever, avoid exposure of application site to direct heat. Do not cut patches. Avoid touching adhesive side, wash hands after use. Abstral: mouth wounds or mucositis. MAOIs, SSRIs, SNRIs, other serotonergic drugs, CNS depressants, inducers or inhibitors of CYP3A4, grapefruit juice, buprenorphine, pentazocine. Instanyl, PecFent: other intranasal drugs. Hypotension, hypertension, somnolence, sedation, dizziness, hallucinations, pruritus, sweating, bradycardia, tachycardia, palpitations, GI upset, urinary retention, headache, confusion, asthenia, fatigue, dyspnoea, respiratory depression, anxiety, anorexia, insomnia, depression, tremor, paraesthesia, muscle spasm, oedema. Oral use: mouth ulceration, dry mouth, flushing. Nasal spray: epistaxis, rhinorrhoea, nasal discomfort, flushing, hot flushes, throat irritation, dysgeusia. Patches: application site reactions. Effentora, PecFent: Report any adverse reaction to CHM.

Additional Notes:

Mezolar Matrix (CD)

Section: Pain Sub Section: Pain, fever (View Prescribing Notes) Drug Class: Opiates Manufacturer: Sandoz Ltd Drug Name: MEZOLAR MATRIX Legal Class: CD

Drug Class: Opiates How Fentanyl Supplied: 12 microgram/hr, 5=8.87. 25 microgram/hr, 5=12.68. Price: 50 microgram/hr, 5=23.69. 75 microgram/hr, 5=33.03.

Drug Name:

MEZOLAR MATRIX 100 microgram/hr, 5=40.71. Transdermal, rounded oblong transparent matrix patches.

Indications:

Severe chronic pain.

Strong opioid-naive patients: Initially 1225 microgram/hr. Opioid tolerant patients: Apply strength of patch according to previous analgesics. See SPC. Adults: Apply patch to non-hairy area of chest or upper arm, remove and replace with new patch every 72 hrs using a different site. Titrate in 12 or 25 microgram/hr increments until pain controlled. Consider other analgesics if dose exceeds 300 microgram/hr. Under 2 years, not recommended. 216 years, opioid tolerant patients only: apply strength of patch according to previous analgesics. See SPC. Children: In young children, apply patch to upper back to minimise potential for removal and monitor adhesion. Remove and replace with new patch every 72 hrs using a different site. Titrate in 12 microgram/hr increments until pain controlled. General Warnings for Fentanyl Severe respiratory depression, severe obstructive lung conditions, severe Contraindications: CNS impairment, bradycardia. Lactation. Fencino, Mezolar Matrix: soya/peanut allergy. Instanyl: previous facial radiotherapy, recurrent epistaxis. COPD, raised intracranial pressure, impaired consciousness, head injury, brain tumour, renal or hepatic impairment, hypovolaemia, hypotension. Monitor for signs of respiratory depression. Myasthenia gravis. Risk of tolerance and dependence (esp in patients with history of drug or alcohol Precautions: dependence); withdraw gradually. Elderly or debilitated patients. Opioid-naive patients. Pregnancy. Dispose of patches and oral units with care. Patches: fever, avoid exposure of application site to direct heat. Do not cut patches. Avoid touching adhesive side, wash hands after use. Abstral: mouth wounds or mucositis. MAOIs, SSRIs, SNRIs, other serotonergic drugs, CNS depressants, Interactions: inducers or inhibitors of CYP3A4, grapefruit juice, buprenorphine, pentazocine. Instanyl, PecFent: other intranasal drugs. Hypotension, hypertension, somnolence, sedation, dizziness, hallucinations, pruritus, sweating, bradycardia, tachycardia, palpitations, GI upset, urinary retention, headache, confusion, asthenia, fatigue, dyspnoea, respiratory depression, anxiety, anorexia, insomnia, Side Effects: depression, tremor, paraesthesia, muscle spasm, oedema. Oral use: mouth ulceration, dry mouth, flushing. Nasal spray: epistaxis, rhinorrhoea, nasal discomfort, flushing, hot flushes, throat irritation, dysgeusia. Patches: application site reactions. Effentora, PecFent: Report any adverse reaction to CHM. Additional Notes:

Cyclimorph (CD)

General Warnings for Fentanyl Section: Pain Sub Section: Pain, fever (View Prescribing Notes) Drug Class: Opiates Manufacturer: Amdipharm Mercury Company Ltd Drug Name: CYCLIMORPH Legal Class: CD

Drug Class: Opiates Cyclimorph 10morphine tartrate 10mg, cyclizine tartrate 50mg/ml. How Supplied: Cyclimorph 15morphine tartrate 15mg, cyclizine tartrate 50mg/ml Cyclimorph 10, 5 x 1ml amp=8.77. Price: Cyclimorph 15, 5 x 1ml amp=9.12. Indications: Moderate to severe pain where reduction of nausea is required. Adults: 1020mg morphine tartrate by sc, im or iv inj not more frequently than every four hrs. Max 3 doses in 24 hrs. Children: Not recommended. General Warnings for Morphine + cyclizine Respiratory depression, obstructed airways, heart failure secondary to chronic lung disease, moderate Contraindications: to severe renal impairment, severe hepatic impairment, ulcerative colitis, acute alcohol intoxication, head injury, raised intracranial pressure. Hypothyroidism, adrenocortical insufficiency, hypopituitarism, prostatic hypertrophy, shock, diabetes, phaeochromocytoma, severe heart failure, Precautions: glaucoma, obstructive disease of GI tract. Risk of tolerance and dependence. Elderly, debilitated. Pregnancy, labour, lactation. MAOIs, CNS depressants, phenothiazines, Interactions: diuretics, propranolol, anticholinergics. Drowsiness, dry mouth, blurred vision, Side Effects: constipation, respiratory depression, orthostatic hypotension.

Alfenta

CII Rx only

Alfenta Description
Alfenta (Alfentanil hydrochloride) Injection is an opioid analgesic chemically designated as N - [1 - [2 - (4 - ethyl - 4,5 - dihydro - 5 - oxo - 1H - tetrazol - 1 - yl)ethyl] - 4 (methoxymethyl) - 4 - piperidinyl] - N - phenylpropanamide monohydrochloride (1:1) with a molecular weight of 452.98 and an n-octanol:water partition coefficient of 128:1 at pH 7.4. The structural formula of Alfenta is:
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Alfenta is a sterile, non-pyrogenic, preservative free aqueous solution containing Alfentanil hydrochloride equivalent to 500 g per mL of Alfentanil base for intravenous injection. The solution, which contains sodium chloride for isotonicity, has a pH range of 4-6. Each mL contains: Active: Alfentanil base 500 mcg. Inactive: Sodium Chloride 9 mg and Water for Injection Q.S.

Alfenta - Clinical Pharmacology

Alfenta (Alfentanil hydrochloride) is an opioid analgesic with a rapid onset of action.

At doses of 8-40 mcg/kg for surgical procedures lasting up to 30 minutes, Alfenta provides analgesic protection against hemodynamic responses to surgical stress with recovery times generally comparable to those seen with equipotent fentanyl dosages. For longer procedures, doses of up to 75 mcg/kg attenuate hemodynamic responses to laryngoscopy, intubation and incision, with recovery time comparable to fentanyl. At doses of 50-75 mcg/kg followed by a continuous infusion of 0.5-3 mcg/kg/min, Alfenta attenuates the catecholamine response with more rapid recovery and reduced need for postoperative analgesics as compared to patients administered enflurane. At doses of 5 mcg/kg, Alfenta provides analgesia for the conscious but sedated patient. Based on patient response, doses higher than 5 mcg/kg may be needed. Elderly or debilitated patients may require lower doses. High intrasubject and intersubject variability in the pharmacokinetic disposition of Alfenta has been reported. The pharmacokinetics of Alfenta can be described as a three-compartment model with sequential distribution half-lives of 1 and 14 minutes; and a terminal elimination half-life of 90-111 minutes (as compared to a terminal elimination half-life of approximately 475 minutes for fentanyl and approximately 265 minutes for sufentanil at doses of 250 mcg). The liver is the major site of biotransformation. Alfenta has an apparent volume of distribution of 0.4-1 L/kg, which is approximately onefourth to one-tenth that of fentanyl, with an average plasma clearance of 5 mL/kg/min as compared to approximately 8 mL/kg/min for fentanyl. Only 1.0% of the dose is excreted as unchanged drug; urinary excretion is the major route of elimination of metabolites. Plasma protein binding of Alfenta is approximately 92%. In one study involving 15 patients administered Alfenta with nitrous oxide/oxygen, a narrow range of plasma Alfenta concentrations, approximately 310-340 ng/mL, was shown to provide adequate anesthesia for intra-abdominal surgery, while lower concentrations, approximately 190 ng/mL, blocked responses to skin closure. Plasma concentrations between 100-200 ng/mL provided adequate anesthesia for superficial surgery. Alfenta has an immediate onset of action. At dosages of approximately 105 mcg/kg, Alfenta produces hypnosis as determined by EEG patterns; an anesthetic ED90 of 182 mcg/kg for Alfenta in unpremedicated patients has been determined, based upon the ability to block response to placement of a nasopharyngeal airway. Based on clinical trials, induction dosage requirements range from 130-245 mcg/kg. For procedures lasting 30-60 minutes, loading dosages of up to 50 mcg/kg produce the hemodynamic response to endotracheal intubation and skin incision as comparable to those from fentanyl. A pre-intubation loading dose of 5075 mcg/kg prior to a continuous infusion attenuates the response to laryngoscopy, intubation and incision. Subsequent administration of Alfenta infusion administered at a rate of 0.5-3 mcg/kg/min with nitrous oxide/oxygen attenuates sympathetic responses to surgical stress with more rapid recovery than enflurane. Requirements for volatile inhalation anesthetics were reduced by thirty to fifty percent during the first 60 minutes of maintenance in patients administered anesthetic doses (above 130 mcg/kg) of Alfenta as compared to patients given doses of 4-5 mg/kg thiopental for anesthetic induction. At anesthetic induction dosages, Alfenta provides a deep level of

anesthesia during the first hour of anesthetic maintenance and provides attenuation of the hemodynamic response during intubation and incision. Following an anesthetic induction dose of Alfenta, requirements for Alfenta infusion are reduced by 30 to 50% for the first hour of maintenance. Patients with compromised liver function and those over 65 years of age have been found to have reduced plasma clearance and extended terminal elimination for Alfenta, which may prolong postoperative recovery. Repeated or continuous administration of Alfenta produces increasing plasma concentrations and an accumulation of the drug, particularly in patients with reduced plasma clearance. Bradycardia may be seen in patients administered Alfenta. The incidence and degree of bradycardia may be more pronounced when Alfenta is administered in conjunction with nonvagolytic neuromuscular blocking agents or in the absence of anticholinergic agents such as atropine. Administration of intravenous diazepam immediately prior to or following high doses of Alfenta has been shown to produce decreases in blood pressure that may be secondary to vasodilation; recovery may also be prolonged. Patients administered doses up to 200 mcg/kg of Alfenta have shown no significant increase in histamine levels and no clinical evidence of histamine release. Skeletal muscle rigidity is related to the dose and speed of administration of Alfenta. Muscular rigidity will occur with an immediate onset following anesthetic induction dosages. Preventative measures (see WARNINGS) may reduce the rate and severity. The duration and degree of respiratory depression and increased airway resistance usually increase with dose, but have also been observed at lower doses. Although higher doses may produce apnea and a longer duration of respiratory depression, apnea may also occur at low doses. During monitored anesthesia care (MAC), attention must be given to the respiratory effects of Alfenta Injection. Decreased oxygen saturation, apnea, decreased respiratory rate, and upper airway obstruction can occur. (See WARNINGS)
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Indications and Usage for Alfenta

Alfenta (Alfentanil hydrochloride) is indicated:

as an analgesic adjunct given in incremental doses in the maintenance of anesthesia with barbiturate/nitrous oxide/oxygen.

as an analgesic administered by continuous infusion with nitrous oxide/oxygen in the maintenance of general anesthesia.

as a primary anesthetic agent for the induction of anesthesia in patients undergoing general surgery in which endotracheal intubation and mechanical ventilation are required.

as the analgesic component for monitored anesthesia care (MAC).

SEE DOSAGE CHART FOR MORE COMPLETE INFORMATION ON THE USE OF Alfenta.

Contraindications
Alfenta (Alfentanil hydrochloride) is contraindicated in patients with known hypersensitivity to the drug or known intolerance to other opioid agonists.

Warnings
Alfenta SHOULD BE ADMINISTERED ONLY BY PERSONS SPECIFICALLY TRAINED IN THE USE OF INTRAVENOUS AND GENERAL ANESTHETIC AGENTS AND IN THE MANAGEMENT OF RESPIRATORY EFFECTS OF POTENT OPIOIDS. AN OPIOID ANTAGONIST, RESUSCITATIVE AND INTUBATION EQUIPMENT AND OXYGEN SHOULD BE READILY AVAILABLE. BECAUSE OF THE POSSIBILITY OF DELAYED RESPIRATORY DEPRESSION, MONITORING OF THE PATIENT MUST CONTINUE WELL AFTER SURGERY. Alfenta (Alfentanil hydrochloride) administered in initial dosages up to 20 mcg/kg may cause skeletal muscle rigidity, particularly of the truncal muscles. The incidence and severity of muscle rigidity is usually dose-related. Administration of Alfenta at anesthetic induction dosages (above 130 mcg/kg) will consistently produce muscular rigidity with an immediate onset. The onset of muscular rigidity occurs earlier than with other opioids. Alfenta may produce muscular rigidity that involves all skeletal muscles, including those of the neck and

extremities. The incidence may be reduced by: 1) routine methods of administration of neuromuscular blocking agents for balanced opioid anesthesia; 2) administration of up to 1/4 of the full paralyzing dose of a neuromuscular blocking agent just prior to administration of Alfenta at dosages up to 130 mcg/kg; following loss of consciousness, a full paralyzing dose of a neuromuscular blocking agent should be administered; or 3) simultaneous administration of Alfenta and a full paralyzing dose of a neuromuscular blocking agent when Alfenta is used in rapidly administered anesthetic dosages (above 130 mcg/kg). The neuromuscular blocking agent used should be appropriate for the patient's cardiovascular status. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered Alfenta. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. PATIENTS RECEIVING MONITORED ANESTHESIA CARE (MAC) SHOULD BE CONTINUOUSLY MONITORED BY PERSONS NOT INVOLVED IN THE CONDUCT OF THE SURGICAL OR DIAGNOSTIC PROCEDURE; OXYGEN SUPPLEMENTATION SHOULD BE IMMEDIATELY AVAILABLE AND PROVIDED WHERE CLINICALLY INDICATED; OXYGEN SATURATION SHOULD BE CONTINUOUSLY MONITORED; THE PATIENT SHOULD BE OBSERVED FOR EARLY SIGNS OF HYPOTENSION, APNEA, UPPER AIRWAY OBSTRUCTION AND/OR OXYGEN DESATURATION. Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported for other opioid analgesics, and rarely with Alfentanil. Therefore when Alfentanil is administered to patients who have received MAO inhibitors within 14 days, appropriate monitoring and ready availability of vasodilators and beta-blockers for the treatment of hypertension is recommended.

Precautions
DELAYED RESPIRATORY DEPRESSION, RESPIRATORY ARREST, BRADYCARDIA, ASYSTOLE, ARRHYTHMIAS AND HYPOTENSION HAVE ALSO BEEN REPORTED. THEREFORE, VITAL SIGNS MUST BE MONITORED CONTINUOUSLY.
General

The initial dose of Alfenta (Alfentanil hydrochloride) should be appropriately reduced in elderly and debilitated patients. The effect of the initial dose should be considered in determining supplemental doses. In obese patients (more than 20% above ideal total body weight), the dosage of Alfenta should be determined on the basis of lean body weight. In one clinical trial, the dose of Alfenta required to produce anesthesia, as determined by appearance of delta waves in EEG, was 40% lower in geriatric patients than that needed in healthy young patients. In patients with compromised liver function and in geriatric patients, the plasma clearance of Alfenta may be reduced and postoperative recovery may be prolonged.

Induction doses of Alfenta should be administered slowly (over three minutes). Administration may produce loss of vascular tone and hypotension. Consideration should be given to fluid replacement prior to induction. Diazepam administered immediately prior to or in conjunction with high doses of Alfenta may produce vasodilation, hypotension and result in delayed recovery. Bradycardia produced by Alfenta may be treated with atropine. Severe bradycardia and asystole have been successfully treated with atropine and conventional resuscitative methods. The hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required should be considered in the selection of a neuromuscular blocking agent. Following an anesthetic induction dose of Alfenta, requirements for volatile inhalation anesthetics or Alfenta infusion are reduced by 30 to 50% for the first hour of maintenance. Alfenta infusions should be discontinued at least 10-15 minutes prior to the end of surgery during general anesthesia. During administration of Alfenta for Monitored Anesthesia Care (MAC), infusions may be continued to the end of the procedure. Respiratory depression caused by opioid analgesics can be reversed by opioid antagonists such as naloxone. Because the duration of respiratory depression produced by Alfenta may last longer than the duration of the opioid antagonist action, appropriate surveillance should be maintained. As with all potent opioids, profound analgesia is accompanied by respiratory depression and diminished sensitivity to CO2 stimulation which may persist into or recur in the postoperative period. Intraoperative hyperventilation may further alter postoperative response to CO2. Appropriate postoperative monitoring should be employed, particularly after infusions and large doses of Alfenta, to ensure that adequate spontaneous breathing is established and maintained in the absence of stimulation prior to discharging the patient from the recovery area.
Head Injuries

Alfenta should be used with caution in patients with head injury or increased intracranial pressure, due to the increased risk of respiratory depression. As with all opioids, Alfenta may obscure the clinical course of patients with head injuries and should be used only if clinically indicated.
Impaired Respiration

Alfenta should be used with caution in patients with pulmonary disease, decreased respiratory reserve or potentially compromised respiration. In such patients, opioids may additionally decrease respiratory drive and increase airway resistance. During anesthesia, this can be managed by assisted or controlled respiration.
Impaired Hepatic or Renal Function

In patients with liver or kidney dysfunction, Alfenta should be administered with caution due to the importance of these organs in the metabolism and excretion of Alfenta.

Drug Interactions

Both the magnitude and duration of central nervous system and cardiovascular effects may be enhanced when Alfenta is administered in combination with other CNS depressants such as barbiturates, tranquilizers, opioids, or inhalation general anesthetics. Postoperative respiratory depression may be enhanced or prolonged by these agents. In such cases of combined treatment, the dose of one or both agents should be reduced. Limited clinical experience indicates that requirements for volatile inhalation anesthetics are reduced by 30 to 50% for the first sixty (60) minutes following Alfenta induction. The concomitant use of erythromycin with Alfenta can significantly inhibit Alfenta clearance and may increase the risk of prolonged or delayed respiratory depression. Cimetidine reduces the clearance of Alfenta. Therefore smaller Alfenta doses will be required with prolonged administration and the duration of action of Alfenta may be extended. Perioperative administration of drugs affecting hepatic blood flow or enzyme function may reduce plasma clearance and prolong recovery.
Carcinogenesis, Mutagenesis and Impairment of Fertility

No long-term animal studies of Alfenta have been performed to evaluate carcinogenic potential. No structural chromosome mutations were produced in the in vivo micronucleus test in female rats at single intravenous doses of Alfenta as high as 20 mg/kg body weight (approximately 40 times the upper human dose), equivalent to a dose of 103 mg/m2 body surface area. No dominant lethal mutations were produced in the in vivo dominant lethal test in male and female mice at the maximum intravenous dose of 20 mg/kg (60 mg/m2). No mutagenic activity was revealed in the in vitro Ames Salmonella typhimurium test, with and without metabolic activation.
Pregnancy Category C

Alfenta has been shown to have an embryocidal effect in rats and rabbits when given in doses 2.5 times the upper human dose for a period of 10 days to over 30 days. These effects could have been due to maternal toxicity (decreased food consumption with increased mortality) following prolonged administration of the drug. No evidence of teratogenic effects has been observed after administration of Alfenta in rats or rabbits. There are no adequate and well-controlled studies in pregnant women. Alfenta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery

There are insufficient data to support the use of Alfenta in labor and delivery. Placental transfer of the drug has been reported; therefore, use in labor and delivery is not recommended.

Nursing Mothers

In one study of nine women undergoing postpartum tubal ligation, significant levels of Alfenta were detected in colostrum four hours after administration of 60 mcg/kg of Alfenta, with no detectable levels present after 28 hours. Caution should be exercised when Alfenta is administered to a nursing woman.
Pediatric Use

Adequate data to support the use of Alfenta in children under 12 years of age are not presently available.

Adverse Reactions
The most common adverse reactions of opioids are respiratory depression and skeletal muscle rigidity, particularly of the truncal muscles. Alfenta may produce muscular rigidity that involves the skeletal muscles of the neck and extremities. See CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS on the management of respiratory depression and skeletal muscle rigidity. The adverse experience profile from 696 patients receiving Alfenta for Monitored Anesthesia Care (MAC) is similar to the profile established with Alfenta during general anesthesia. Respiratory events reported during MAC included hypoxia, apnea, and bradypnea. Other adverse events reported by patients receiving Alfenta for MAC, in order of decreasing frequency, were nausea, hypotension, vomiting, pruritus, confusion, somnolence and agitation. The following adverse reaction information is derived from controlled and open clinical trials in 785 patients who received intravenous Alfenta during induction and maintenance of general anesthesia. The controlled trials included treatment comparisons with fentanyl, thiopental sodium, enflurane, saline placebo and halothane. The incidence of certain side effects is influenced by the type of use, e.g., chest wall rigidity has a higher reported incidence in clinical trials of Alfentanil induction, and by the type of surgery, e.g., nausea and vomiting have a higher reported incidence in patients undergoing gynecologic surgery. The overall reports of nausea and vomiting with Alfenta were comparable to fentanyl.
Incidence Greater than 1% - Probably Causally Related (Derived from clinical trials) * Incidence 3% to 9% All others 1% to 3% Gastrointestinal: nausea (28%), vomiting (18%) arrhythmia, bradycardia (14%), hypertension (18%), hypotension (10%),

Cardiovascular:

tachycardia (12%) Musculoskeletal: Respiratory: Central Nervous System: chest wall rigidity (17%), skeletal muscle movements* apnea*, postoperative respiratory depression blurred vision, dizziness*, sleepiness/postoperative sedation

Incidence Less than 1% - Probably Causally Related (Derived from clinical trials)

Adverse events reported in post-marketing surveillance, not seen in clinical trials, are italicized.
* Incidence 0.3% to 1% Body as a whole: Central Nervous System: Dermatological: Injection Site: Musculoskeletal: Respiratory: Ads by Google anaphylaxis headache*, myoclonic movements, postoperative confusion*, postoperative euphoria*, shivering* itching*, urticaria* pain* skeletal muscle rigidity of neck and extremities bronchospasm, hypercarbia*, laryngospasm*

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Drug Abuse and Dependence

Alfenta (Alfentanil hydrochloride) is a Schedule II controlled drug substance that can produce drug dependence of the morphine type and therefore has the potential for being abused. Opioid analgesics have been associated with abuse and dependence in health care providers and others with ready access to such drugs. Alfenta should be handled accordingly.

Overdosage
Overdosage would be manifested by extension of the pharmacological actions of Alfenta (Alfentanil hydrochloride) (see CLINICAL PHARMACOLOGY) as with other potent opioid analgesics. No experience of overdosage with Alfenta was reported during clinical trials. The intravenous LD50 of Alfenta is 43-51 mg/kg in rats, 72-74 mg/kg in mice, 72-82 mg/kg in guinea pigs and 60-88 mg/kg in dogs. Intravenous administration of an opioid antagonist such as naloxone should be employed as a specific antidote to manage respiratory depression. The duration of respiratory depression following overdosage with Alfenta may be longer than the duration of action of the opioid antagonist. Administration of an opioid antagonist should not preclude immediate establishment of a patent airway, administration of oxygen, and assisted or controlled ventilation as indicated for hypoventilation or apnea. If respiratory depression is associated with muscular rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled ventilation. Intravenous fluids and vasoactive agents may be required to manage hemodynamic instability.

Alfenta Dosage and Administration

The dosage of Alfenta (Alfentanil hydrochloride) should be individualized and titrated to the desired effect in each patient according to body weight, physical status, underlying pathological condition, use of other drugs, and type and duration of surgical procedure and anesthesia. In obese patients (more than 20% above ideal total body weight), the dosage of Alfenta should be determined on the basis of lean body weight. The dose of Alfenta should be reduced in elderly or debilitated patients (see PRECAUTIONS). Vital signs should be monitored routinely. See Dosage Guidelines for the use of Alfenta: 1) by incremental injection as an analgesic adjunct to anesthesia with barbiturate/nitrous oxide/oxygen for short surgical procedures (expected duration of less than one hour); 2) by continuous infusion as a maintenance analgesic with nitrous oxide/oxygen for general surgical procedures; and 3) by intravenous injection in anesthetic doses for the induction of anesthesia for general surgical procedures with a minimum expected duration of 45 minutes; and 4) by intravenous injection as the analgesic component for monitored anesthesia care (MAC).
DOSAGE GUIDELINES DOSAGE SHOULD BE INDIVIDUALIZED AND TITRATED FOR USE DURING GENERAL ANESTHESIA

DOSAGE GUIDELINES DOSAGE SHOULD BE INDIVIDUALIZED AND TITRATED FOR USE DURING GENERAL ANESTHESIA Induction of Analgesia: 8-20 mcg/kg Maintenance of Analgesia: 3-5 mcg/kg q 5-20 min or 0.5 to 1 mcg/kg/min Total dose: 8-40 mcg/kg

SPONTANEOUSLY BREATHING/ASSISTED VENTILATION

ASSISTED OR CONTROLLED VENTILATION Incremental Injection (To attenuate response to laryngoscopy and intubation) Induction of Analgesia: 20-50 mcg/kg Maintenance of Analgesia: 5-15 mcg/kg q 520 min Total dose: Up to 75 mcg/kg

Infusion rates are variable and should be titrated to the desired clinical effect. SEE INFUSION DOSAGE GUIDELINES BELOW. Continuous Infusion Induction of Analgesia: 50-75 mcg/kg (To provide attenuation of response to Maintenance of Analgesia: 0.5 to 3 mcg/kg/min (Average rate 1 to 1.5 intubation and incision) mcg/kg/min) Total dose: Dependent on duration of procedure Induction of Anesthesia: 130-245 mcg/kg Maintenance of Anesthesia: 0.5 to 1.5 mcg/kg/min or general anesthetic Total dose: Dependent on duration of procedure At these doses, truncal rigidity should be expected and a muscle relaxant should be utilized. Administer slowly (over 3 minutes). Concentration of inhalation agents reduced by 30-50% for initial hour.

Anesthetic Induction

Induction of MAC: 3-8 mcg/kg MONITORED ANESTHESIA CARE (MAC) Maintenance of MAC: 3-5 mcg/kg q 5-20 min (For sedated and responsive, or 0.25 to 1 mcg/kg/min spontaneously breathing patients) Total dose: 3-40 mcg/kg

INFUSION DOSAGE Continuous Infusion: 0.5-3 mcg/kg/min administered with nitrous oxide/oxygen in patients undergoing general surgery. Following an anesthetic induction dose of Alfenta, infusion rate requirements are reduced by 30-50% for the first hour of maintenance. Changes in vital signs that indicate a response to surgical stress or lightening of anesthesia may be controlled by increasing the Alfentanil to a maximum of 4 mcg/kg/min and/or administration of bolus doses of 7 mcg/kg. If changes are not controlled after three bolus doses given over a five minute period, a barbiturate, vasodilator, and/or inhalation agent should be used. Infusion rates should always be adjusted downward in the absence of these signs until there is some response to surgical stimulation. Rather than an increase in infusion rate, 7 mcg/kg bolus doses of Alfenta or a potent inhalation agent should be administered in response to signs of lightening of anesthesia within the last 15 minutes of surgery. Alfenta infusion should be discontinued at least 10-15 minutes prior to the end of surgery. Usage in Children

Clinical data to support the use of Alfenta in patients under 12 years of age are not presently available. Therefore, such use is not recommended.
Premedication

The selection of preanesthetic medications should be based upon the needs of the individual patient.
Neuromuscular Blocking Agents

The neuromuscular blocking agent selected should be compatible with the patient's condition, taking into account the hemodynamic effects of a particular muscle relaxant and the degree of skeletal muscle relaxation required (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS sections). In patients administered anesthetic (induction) dosages of Alfenta, it is essential that qualified personnel and adequate facilities are available for the management of intraoperative and postoperative respiratory depression. Also see WARNINGS and PRECAUTIONS sections. For purposes of administering small volumes of Alfenta accurately, the use of a tuberculin syringe or equivalent is recommended.

The physical and chemical compatibility of Alfenta have been demonstrated in solution with normal saline, 5% dextrose in normal saline, 5% dextrose in water and Lactated Ringers. Clinical studies of Alfenta infusion have been conducted with Alfenta diluted to a concentration range of 25 mcg/mL to 80 mcg/mL. As an example of the preparation of Alfenta for infusion, 20 mL of Alfenta added to 230 mL of diluent provides 40 mcg/mL solution of Alfenta. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
SAFETY AND HANDLING

Alfenta (Alfentanil hydrochloride) is supplied in individually sealed dosage forms which pose no known risk to health-care providers having incidental contact. Accidental dermal exposure to Alfenta should be treated by rinsing the affected area with water. Protect from light. Storage: Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature].

How is Alfenta Supplied

Alfenta (Alfentanil hydrochloride) Injection for intravenous use. Each mL Contains: Active: Alfentanil base 500 mcg. Inactives: Sodium Chloride 9 mg and WFI Q.S Alfenta Injection is available as: NDC 11098-060-02, 2 mL Ampule in packages of 10 NDC 11098-060-05, 5 mL Ampule in packages of 10 NDC 11098-060-10, 10 mL Ampule in packages of 5 NDC 11098-060-20, 20 mL Ampule in packages of 5 U.S. Patent No. 4,167,574 May 1995, November 1995 TAYLOR PHARMACEUTICALS AN AKORN COMPANY Decatur, IL 62522 AFA0N Rev. 06/05
Alfenta Alfentanil hydrochloride injection Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:11098060

Route of Administration

INTRAVENOUS

DEA Schedule

CII

Indications and Usage for Ionsys

Ionsys is indicated for the short-term management of acute postoperative pain in adult patients requiring opioid analgesia during hospitalization. Patients should be titrated to an acceptable level of analgesia before initiating treatment with Ionsys. Ionsys is not intended for home use and is, therefore, inappropriate for use in patients once they have been discharged from the hospital. It is not recommended for patients under the age of 18 years (see WARNINGS and PRECAUTIONS)

Numorphan
Generic Name: oxymorphone (OX-i-MOR-fone) Brand Name: Opana
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Numorphan is used for:

Treating moderate to severe pain. It may be used before surgery to cause sedation and reduce anxiety. It may also be used for other conditions as determined by your doctor. Numorphan is a narcotic pain reliever. It works in the brain and nervous system to reduce pain. It may also affect other body systems (eg, respiratory, circulatory) at higher doses.

Do NOT use Numorphan if:

you are allergic to any ingredient in Numorphan or any other codeine- or morphine-related medicine (eg, oxycodone) you have known or suspected stomach or bowel blockage (eg, paralytic ileus) you have slow or difficult breathing, fluid in the lungs due to chemical irritation, high levels of carbon dioxide in the blood (hypercapnia or hypercarbia), or severe asthma, or you are having an asthma attack you have moderate to severe liver problems you are taking mixed agonist/antagonist analgesic medicines (eg, buprenorphine,

butorphanol, pentazocine) or sodium oxybate (GHB) you are taking or have taken a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) within the last 14 days

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

Some medical conditions may interact with Numorphan. 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 a history of chronic obstructive pulmonary disease (COPD) or other lung or breathing problems (eg, asthma, emphysema, bronchitis), sleep apnea, curvature of the spine (eg, kyphoscoliosis), heart problems (eg, cor pulmonale), hypercapnia or hypercarbia, low levels of oxygen in the blood (hypoxia), low blood pressure, dehydration, or low blood volume if you have severe drowsiness, a recent head injury, increased pressure in the brain, growths in the brain (eg, tumors), or a history of seizures if you have liver or kidney problems, thyroid problems, adrenal gland problems (eg, Addison disease), stomach pain, stomach or bowel problems (eg, inflammation), gallbladder or pancreas problems, a blockage of the bladder, trouble urinating, constipation, or an enlarged prostate, or if you have had recent stomach or bowel surgery if you drink alcohol, have symptoms of alcohol withdrawal, or have a history of suicidal thoughts or attempts if you or a member of your family has a history of mood or mental problems (eg, anxiety, depression, hallucinations), or alcohol or other substance abuse or dependence if you have poor health or are in shock, are very overweight, or have recently had or will be having surgery

if you are taking carisoprodol

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

Phenothiazines (eg, chlorpromazine) because the risk of low blood pressure may be increased Cimetidine or sodium oxybate (GHB) because the risk of side effects, such as severe drowsiness, slow or difficult breathing, coma, or confusion, may be increased Anticholinergics (eg, scopolamine, benztropine) because the risk of severe constipation or trouble urinating may be increased MAOIs (eg, phenelzine) because the risk of a severe reaction, including fever, seizures, and coma, may be increased Mixed agonist/antagonist analgesics (eg, buprenorphine, butorphanol, nalbuphine, pentazocine) or naltrexone because they may decrease Numorphan's effectiveness and withdrawal may occur

This may not be a complete list of all interactions that may occur. Ask your health care provider if Numorphan 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.
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How to use Numorphan:

Use Numorphan as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Numorphan is usually administered as an injection at your doctor's office, hospital, or clinic. If you will be using Numorphan at home, a health care provider will teach you how to use it. Be sure you understand how to use Numorphan. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions. Do not use Numorphan if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged. Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal. If you have been taking Numorphan regularly, do not suddenly stop taking Numorphan. You

may have an increased risk of withdrawal symptoms (eg, nausea, sweating, pain). If you need to stop Numorphan, your doctor will gradually lower your dose. Numorphan is usually used as needed. If you forget to use a dose of Numorphan and you still have pain, use it when you remember as directed by your doctor. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Numorphan.

Important safety information:

Numorphan may cause dizziness, drowsiness, blurred vision, or light-headedness. These effects may be worse if you take it with alcohol or certain medicines. Use Numorphan with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it. Do not drink alcohol or take medicines (prescription or nonprescription) that contain alcohol while you are using Numorphan. Check with your pharmacist if you have questions about whether any of your medicines contain alcohol. Check with your doctor before you use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Numorphan; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness. Numorphan may cause dizziness, light-headedness, or fainting. Alcohol, hot weather, exercise, and fever can increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Also, sit or lie down at the first sign of dizziness, light-headedness, or weakness. Numorphan may be habit forming. Do NOT take more than the recommended dose, change your dose, use more often than prescribed, or use for longer than prescribed without checking with your doctor. Misuse or abuse of Numorphan may cause severe side effects, including severe breathing problems, seizures, coma, and possibly death. Numorphan may cause constipation. Talk with your doctor or pharmacist about using a stool softener or laxative to prevent constipation. It is also important to maintain a diet adequate in fiber, drink plenty of water, and exercise to prevent constipation. If you become constipated while taking Numorphan, talk with your doctor or pharmacist. If your pain continues or becomes worse, or if you have side effects that concern you, contact your doctor. Tell your doctor or dentist before you receive any medical or dental care, emergency care, or surgery. Use Numorphan with caution in the ELDERLY; they may be more sensitive to its effects, especially breathing problems, drowsiness, dizziness, confusion, and nausea. Use Numorphan with extreme caution in CHILDREN younger than 18 years old; safety and effectiveness in these children have not been confirmed. PREGNANCY AND BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Numorphan while you are pregnant. Longterm use of Numorphan during pregnancy may cause dependence in the fetus or newborn. Discuss any questions or concerns with your doctor. It is not known if Numorphan is found in breast milk. If you are or will be breast-feeding while you are using Numorphan, check with your doctor. Discuss any possible risks to your baby.

When used for long periods of time or at high doses, Numorphan may not work as well and may require higher doses to obtain the same effect as when originally taken. This is known as TOLERANCE. Talk with your doctor if Numorphan stops working well. Do not take more

than prescribed. When used for long periods of time or at high doses, some people develop a need to continue taking Numorphan. This is known as DEPENDENCE or addiction. If you are taking Numorphan regularly, do not suddenly stop taking it without checking with your doctor. WITHDRAWAL symptoms have occurred when Numorphan is suddenly stopped and may include anxiety; diarrhea; fever, runny nose, or sneezing; goose bumps and abnormal skin sensations; nausea and vomiting; pain; rigid muscles; seeing, hearing, or feeling things that are not there; shivering or tremors; sweating; and trouble sleeping. Contact your doctor if you notice any of these symptoms after stopping Numorphan.

Possible side effects of Numorphan:

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: Constipation; dizziness; drowsiness; dry mouth; headache; mild itching; nausea; sweating; 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); chest pain; confusion; fainting; fast, slow, or irregular heartbeat; fever; hallucinations; mental or mood changes (eg, agitation, depression); seizures; severe or persistent constipation, stomach pain, or vomiting; severe or persistent dizziness, drowsiness, or headache; shallow, slowed, or difficult breathing; shortness of breath; trouble urinating; unusual swelling; vision changes (eg, blurred vision). 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.
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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. Symptoms may include bluish skin; chest, jaw, or arm pain; cold and clammy skin; coma; difficult, shallow, or slow breathing; fainting; limp muscles; pinpoint pupils; severe drowsiness or dizziness; shortness of breath; slow or irregular heartbeat; sudden, severe nausea or vomiting; sudden, unusual sweating or weakness.
Proper storage of Numorphan:

Numorphan is usually handled and stored by a health care provider. If you are using Numorphan at home, store Numorphan as directed by your pharmacist or health care provider. Keep Numorphan out of the reach of children and away from pets.

General information:

If you have any questions about Numorphan, please talk with your doctor, pharmacist, or other health care provider. Numorphan 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 should not be used to decide whether or not to take Numorphan or any other medicine. Only your health care provider has the knowledge and training to decide which medicines are right for you. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Numorphan. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Numorphan. This information is not specific medical advice and does not replace information you receive from your health care provider. You must talk with your healthcare provider for complete information about the risks and benefits of using Numorphan.
Issue Date: September 4, 2013 Database Edition 13.3.1.003 Copyright 2013 Wolters Kluwer Health, Inc. http://www.drugs.com/cdi/numorphan.html Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength

Alfentanil Hydrochloride (Alfentanil) Inactive Ingredients Ingredient Name sodium chloride water Packaging # Item Code 1 NDC:11098-060-02 1 2 NDC:11098-060-05 2 3 NDC:11098-060-10 3 4 NDC:11098-060-20 4

Alfentanil

500 ug in 1 mL

Strength 9 mg in 1 mL

Package Description 10 AMPULE (10 AMPULE) in 1 PACKAGE 2 mL (2 MILLILITER) in 1 AMPULE 10 AMPULE (10 AMPULE) in 1 PACKAGE 5 mL (5 MILLILITER) in 1 AMPULE 5 AMPULE (5 AMPULE) in 1 PACKAGE 10 mL (10 MILLILITER) in 1 AMPULE 5 AMPULE (5 AMPULE) in 1 PACKAGE 20 mL (20 MILLILITER) in 1 AMPULE

Labeler - TAYLOR PHARMACEUTICALS Revised: 02/2008

TAYLOR PHARMACEUTICALS

Ionsys
Generic Name: fentanyl hydrochloride Dosage Form: transdermal system
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Ionsys (fentanyl iontophoretic transdermal system) 40 mcg*/activation

CII Patient-activated * Equals to 44.4 mcg fentanyl HCl Ionsys should only be used for the treatment of hospitalized patients. Treatment with Ionsys should be discontinued before patients are discharged from the hospital. Treatment with fentanyl, the active component of Ionsys, may result in potentially lifethreatening respiratory depression and death. To avoid potential overdosing, only the patient should activate Ionsys dosing. Inappropriate use of Ionsys, leading to ingestion or contact with mucous membranes or unintended exposure to the fentanyl hydrogel could lead to the absorption of a potentially fatal dose of fentanyl. Therefore, the hydrogels should not come into contact with fingers or mouth. Ionsys contains fentanyl, a potent opioid agonist and Schedule II controlled substance with high potential for abuse similar to hydromorphone, methadone, morphine, and oxycodone. Fentanyl can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Ionsys in situations where the Health Care Professional is concerned about an increased risk of misuse, abuse, or diversion. After the maximum dosage administration, a significant amount of fentanyl remains in the device. Ionsys should always be kept out of reach of children.

Ionsys Description
Ionsys (fentanyl iontophoretic transdermal system) is a patient-controlled iontophoretic transdermal system providing on-demand systemic delivery of fentanyl, an opioid agonist, for up to 24 hours or a maximum of 80 doses, whichever comes first. The chemical name is propanamide, N-phenyl-N-[1-(2-phenylethyl)-4- piperidinyl] monohydrochloride. The structural formula is:

The molecular weight of fentanyl hydrochloride is 372.93, and the empirical formula is C22H28N2OHCl. The n-octanol:water partition coefficient is 860:1; the pKa is 8.4.
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The active ingredient in Ionsys is fentanyl HCl, which is equivalent to 40 mcg per dose of fentanyl free base. Ionsys contains 10.8 mg of fentanyl hydrochloride equivalent to 9.7 mg of fentanyl. Ionsys is designed to deliver a 40-mcg dose of fentanyl (equivalent to 44.4 mcg of fentanyl hydrochloride) over a 10-minute period upon each activation of the dose button (see DOSAGE AND ADMINISTRATION). The inactive ingredients in the Ionsys hydrogels consist of cetylpyridinium chloride, USP; citric acid, USP; polacrilin; polyvinyl alcohol; sodium citrate, USP; sodium chloride, USP; sodium hydroxide; and purified water, USP.
System Components and Structure

Each Ionsys system is composed of a plastic top housing that contains the battery and electronics, and a red plastic bottom housing containing two hydrogel reservoirs and a polyisobutylene skin adhesive. Only one of the hydrogels (the anode, located under the dosing button) contains fentanyl HCl, along with inactive ingredients. The other hydrogel (the cathode) contains only pharmacologically inactive ingredients. The bottom housing has a red tab that is used only for system removal from the skin and during disposal (see DOSAGE AND ADMINISTRATION, Disposal). A siliconized clear, plastic release liner covers the hydrogels and must be removed and discarded prior to placement on the skin. The system is powered by a 3-volt lithium battery.

Ionsys (fentanyl iontophoretic transdermal system)

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Ionsys - Clinical Pharmacology

Pharmacology

Fentanyl is an opioid analgesic. Fentanyl interacts predominantly with the opioid -receptor. These -binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, fentanyl exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. Fentanyl may increase the patient's tolerance for pain and decrease the perception of suffering, although the presence of the pain itself may still be recognized. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Fentanyl depresses the respiratory centers and the cough reflex, and constricts the pupils. Analgesic blood concentrations of fentanyl may cause nausea and vomiting by directly stimulating the chemoreceptor trigger zone, but nausea and vomiting are significantly more common in ambulatory than in recumbent patients, as is postural syncope. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of opioids. Because opioids may increase biliary tract pressure, some patients with biliary colic may experience worsening rather than relief of pain. While opioids generally increase the tone of urinary tract smooth muscle, the net effect tends to be variable, in some cases producing urinary urgency, in others, difficulty in urination. At therapeutic dosages, fentanyl usually does not exert major effects on the cardiovascular system. However, some patients may exhibit orthostatic hypotension and fainting. Histamine assays and skin wheal testing in humans indicate that clinically significant histamine release rarely occurs with fentanyl administration. Assays in humans show no clinically significant histamine release in dosages up to 50 mcg /kg.

Pharmacodynamics Analgesia

When patients titrated themselves to analgesic effect with Ionsys 40 mcg, serum concentrations were in the range of 0.4 to 1.5 ng/mL over the 24-hour dosing period.
Respiratory Effects

Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations and may occur at any time during therapy, especially for patients who have an underlying pulmonary condition or who receive doses of opioids or other CNS drugs associated with hypoventilation in addition to Ionsys. The respiratory effects of Ionsys should be monitored by clinical evaluation, including oxygen saturation, respiratory rate, and degree of sedation. After delivery of the maximum number of doses in the shortest possible time period (80 consecutive doses delivered over approximately 13 hours), the fentanyl serum concentration was in the range of 1.51 to 2.37 ng/mL, which is in the range that could result in respiratory depression. See WARNINGS, PRECAUTIONS and OVERDOSAGE for additional information on respiratory depression.
Cardiovascular Effects

Fentanyl may produce bradycardia.

CNS Effects

Central nervous system effects, such as sedation and depression of respiration, increase with increasing serum fentanyl concentrations.
Pharmacokinetics

Unless otherwise specified, the clinical pharmacology studies described in this section were performed in healthy adult volunteers. Volunteers were administered naltrexone to antagonize the opioid effects of fentanyl.
Absorption

At the initiation of each dose, an electrical current is activated, which moves a dose of fentanyl from the drug-containing reservoir through the skin and into the systemic circulation. Compared to IV fentanyl administration, fentanyl concentrations in blood increase slowly with Ionsys activation and continue to increase for approximately 5 minutes after the completion of each 10-minute dose. The systemic absorption of fentanyl from Ionsys increases as a function of time, and this increase appears to be independent of frequency of dosing. When a dose of 40 mcg is administered at treatment initiation, the amount of fentanyl absorbed is expected to be approximately 16 mcg (see Figures 1A, 1B). In clinical pharmacokinetic studies, on-demand dosing was initiated immediately after Ionsys application. This resulted in absorption of a

40 mcg fentanyl dose by about 10 hours post treatment initiation. Thereafter, a 40-mcg dose of fentanyl is delivered with each activation. After delivery of the maximum number of doses in the shortest possible time period (80 consecutive doses delivered over approximately 13 hours), the average maximum fentanyl serum concentration was 1.94 0.43 ng/mL. Pharmacokinetic data from illustrative dosing regimens are represented in Table 1. When Ionsys was applied without activating the current, the average absorption rate for fentanyl over 24 hours was 2.3 mcg/h. Inter-subject variability in fentanyl AUC following Ionsys treatment (33%) was comparable to IV fentanyl treatment (28%), suggesting that the iontophoretic transdermal system does not add to the inherent between-subject variability in fentanyl AUC. The delivery of fentanyl from Ionsys is similar whether applied on the upper outer arm or the chest. When the system is placed on the lower inner arm, the delivery of fentanyl is approximately 20% lower. Other application sites have not been evaluated.

Table 1 Mean Pharmacokinetic Parameters Based on Representative and Maximum Dosing Regimens (n=23) Dosing Regimen

*AUC for this dosing regimen is value estimated between 23-24 hours **Average AUC over all doses delivered during the treatment duration (13.33 hours) a Representative dosing regimen b Maximum theoretical dosing
Parameter 48a doses (two sequential doses every hour for 23 hours and 20 minutes) 80b sequential doses (one dose every ten minutes for 13 hours and 20 minutes) 0.510.16**

AUC per on-demand 0.570.13* dose (ng/mL) Cmax (ng/mL) Distribution 1.30.3

1.940.43

Fentanyl administered intravenously exhibits a three-compartment disposition model. In healthy volunteers after IV administration, the estimated initial distribution half-life was about 6 minutes; the second distribution half-life was about 1-hour; and the terminal half-life was about 16 hours. The average volume of distribution for fentanyl at steady state following IV administration is 833 L. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%. Fentanyl binds to erythrocytes, 1-acid glycoproteins, and plasma albumin. Binding is independent of drug concentration over the therapeutic range. Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in blood pH may alter ionization of fentanyl and therefore its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood.
Metabolism

In humans, fentanyl is metabolized primarily by cytochrome P450 3A4-mediated Ndealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. The average clearance in healthy subjects following IV administration was observed to be 53 L/h. Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites, with less than 10% representing unchanged drug. Approximately 9% of the dose is recovered in the feces, primarily as metabolites.

A decline in fentanyl concentration after termination of treatment and the terminal half-life is similar following IV administration of fentanyl and Ionsys (see Figure 1B). This suggests a negligible contribution from continued absorption of fentanyl remaining in the skin. Skin does not metabolize fentanyl administered transdermally. This was determined in a human keratinocyte cell assay.
Drug Interactions Agents Affecting Cytochrome P450 3A4

Fentanyl is metabolized mainly via the cytochrome P450 3A4 enzyme (CYP3A4). Therefore, drug interactions may occur when Ionsys is given concurrently with agents that affect CYP3A4 activity. Coadministration with agents that induce CYP3A4 activity, such as rifampin, carbamazepine, phenytoin, and Saint John's Wort, may cause increased clearance of fentanyl and reduce the efficacy of Ionsys. The concomitant use of fentanyl with CYP3A4 inhibitors such as macrolide antibiotics (e.g. erythromycin), azole antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g. ritonavir) may result in a decrease in fentanyl clearance, which could increase or prolong adverse drug effects including serious respiratory depression. In this situation, special patient care and observation are appropriate.
Special Populations

Literature suggests that clearance of fentanyl may be reduced and the terminal half-life prolonged in the elderly (see PRECAUTIONS). In a pharmacokinetic study conducted in 63 healthy volunteers where several demographic factors (age, race, gender, and body mass index) were evaluated, none of these factors had a significant effect on the extent of drug absorption (AUC) following administration of Ionsys.

Clinical Studies
Placebo-controlled Trials

The efficacy and safety of Ionsys for treatment of short-term acute pain were evaluated in three placebo-controlled studies in postoperative patients. The patients were predominantly female (70-83%) and Caucasian (79-84%), and their mean age was 45-54 years (range, 18-90 years). Patients were enrolled while in the recovery room shortly after major surgery (predominantly lower abdominal or orthopedic) if they were expected to require at least 24 hours of parenteral opioid treatment and were not opioid tolerant; their ASA (American Society of Anesthesiologists) physical status was I, II, or III; and their postsurgical recovery was expected to be uncomplicated. Across the trials, 154 patients were ASA I status (21%); 435 patients were ASA II status (60%); and 138 patients were ASA III status (19%). Administration of long-lasting or continuous regional analgesics, or any non-opioid analgesics was not permitted in the studies. Patients who remained in the studies for three or more hours using Ionsys (or the control) for patient-controlled analgesia (PCA) were considered evaluable. In the immediate postoperative period, patients were titrated to comfort with IV fentanyl or morphine per hospital protocol. Once comfortable, patients were randomized and the

Ionsys or matching placebo system was applied. Patients were instructed to use the system for pain relief. Supplemental IV fentanyl was administered by bolus injection as needed to achieve comfort up to three hours post-enrollment. The percentage of patients who used rescue medication during these three hours, as well as the mean amount of rescue medication used, is shown in Table 2 below.
Table 2: Percentage of Patients Requiring Supplemental IV Fentanyl Medication in Hours 03 (Mean Quantity Administered) Ionsys Study 1 Study 2 Study 3 45 % (83 mcg) 48 % (100 mcg) 34 % (78 mcg) Placebo 52 % (102 mcg) 55 % (95 mcg) 36 % (76 mcg)

After Study Hour 3, Ionsys alone or the placebo treatment alone was used to provide analgesia. In each of the three randomized, double-blind, placebo-controlled trials, fewer patients discontinued for lack of efficacy from three hours to twenty-four hours after Ionsys application (see Table 3).
Table 3: Percent (n) of Patients Who Withdrew Due to Inadequate Analgesia Hours 3-24 Study Ionsys n=454 27 % (64/235) 25 % (36/142) 8 % (6/77) Placebo n=273 57 % (116/204) 40 % (19/47) 41 % (9/22) p-value

Study 1 Study 2 Study 3

<0.0001 0.049 0.0001

The last mean pain intensity scores recorded during the 24-hour treatment period are presented in Table 4.
Table 4: Mean Pain Intensity Score Study Ionsys n=454 Placebo n=273 p-value

a Verbal numerical rating score 0-10 at 24 hours or at discontinuation b Visual analogue scale, 0-100 mm at 24 hours or at discontinuation

Table 4: Mean Pain Intensity Score Study Ionsys n=454 3.4 31 21 Placebo n=273 5.3 41 37 p-value

Study 1 (NRSa) Study 2 (VASb) Study 3 (VASb)

<0.0001 0.0474 0.0006

The type of surgical procedure did not influence the trends in efficacy endpoints. The efficacy of Ionsys was similar across the range of body mass indices studied (<25 to40 kg/m2 Body Mass Index). Patients who completed 24 hours of Ionsys treatment in the controlled studies used a wide range of the available 80 doses, with a mean of 29 doses/patient (range of 0-93 doses). The majority of patients (56.5%) used between 11 to 50 doses. One percent of patients required a second system within 24 hours, after exhausting the first system.

Indications and Usage for Ionsys

Ionsys is indicated for the short-term management of acute postoperative pain in adult patients requiring opioid analgesia during hospitalization. Patients should be titrated to an acceptable level of analgesia before initiating treatment with Ionsys. Ionsys is not intended for home use and is, therefore, inappropriate for use in patients once they have been discharged from the hospital. It is not recommended for patients under the age of 18 years (see WARNINGS and PRECAUTIONS).

Contraindications
Ionsys is contraindicated in patients with known hypersensitivity to fentanyl, cetylpyridinium chloride (e.g. Cepacol) or any components of the Ionsys system.

Warnings
Ionsys should be prescribed only by persons knowledgeable in the administration of potent opioids and in the management of patients receiving potent opioids for treatment of pain. Patients treated with Ionsys should be under the supervision of medical personnel with expertise in the detection and management of hypoventilation, including airway management and the use of opioid antagonists. Inappropriate use of Ionsys, leading to ingestion or contact with mucous membranes, or unintended exposure to the fentanyl hydrogel, could lead to the absorption of a potentially fatal dose of fentanyl. Therefore, the hydrogels should not come into contact with fingers or mouth.

The mean terminal elimination half-life of Ionsys is 11 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require continued monitoring after Ionsys removal since serum fentanyl concentrations decline gradually (See Figure 1B). To avoid potential overdosing, only the patient should activate Ionsys. Ionsys should be used only in hospitals, by patients under medical supervision and direction. More than one Ionsys system should not be applied to a patient at the same time. If the fentanyl hydrogel becomes separated from the Ionsys system, contact can be harmful to humans and animals. If the hydrogel becomes separated from the Ionsys system during removal, use gloves or tweezers to remove the hydrogel from the skin and properly dispose of in accordance with state and federal regulations for controlled substances. The skin area that had been in contact with the hydrogel should be thoroughly flushed with water. Do not use soap, alcohol, or other solvents to remove the hydrogel as they may enhance the drug's ability to penetrate the skin. In the event that the Ionsys system falls off, ensure that the entire Ionsys system (i.e. with hydrogel) is collected and properly disposed of. Prior to discharge from the hospital, medical personnel must remove the Ionsys system and dispose of it properly (seeDOSAGE AND ADMINISTRATION, Disposal). After the maximum dosage administration, a significant amount of fentanyl remains in the device.
Misuse, Abuse and Diversion of Opioids

Fentanyl is an opioid agonist of the morphine type. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Fentanyl can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Ionsys in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. 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

Fentanyl may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Precautions
General

Only patients who are able to understand and follow the instructions to operate Ionsys should use the system.

Patients should be titrated to an acceptable level of analgesia before initiating dosing with the Ionsys system. Ionsys should be applied to intact, non-irritated, and non-irradiated skin on the chest or upper outer arm. Care should be taken to avoid exposing Ionsys to water as this could cause the system to fall off or stop working. The error detection circuitry in Ionsys uses a series of audible signals to alert the patient or caregiver when a dose is not being delivered in response to the patient's attempt to activate a dose. Therefore, Ionsys should be used with caution in patients who have high frequency hearing impairment (see DOSAGE AND ADMINISTRATION, Troubleshooting). The testing instructions in the Dosage and Administration section can be used to demonstrate the audible tone for patients if there is any question of the patient's ability to hear the tone. Ionsys contains metal parts and should be removed before an MRI procedure, cardioversion, or defibrillation to avoid damage to the system from the strong electromagnetic fields set up by these procedures. (See DOSAGE AND ADMINISTRATION, Disposal). Ionsys contains radio-opaque components and may interfere with an X-ray image or CAT scan. The low-level electrical current provided by Ionsys does not result in electromagnetic interference with other electromechanical devices like pacemakers or electrical monitoring equipment.
Interactions with other CNS Depressants

The concomitant use of other central nervous system depressants, including other opioids, sedatives, hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, or alcoholic beverages, may produce additive depressant effects. Hypoventilation, hypotension, profound sedation, respiratory depression, coma, or death may result. Therefore, the use of concomitant CNS depressants requires individual adjustment of dosage of the concomitant medication and close observation of the patient. As with other opioid medications, Ionsys may impair the mental and/or physical ability required for the performance of potentially hazardous tasks.
Chronic Opioid Therapy

Ionsys has not been studied in the treatment of breakthrough pain in patients on chronic opioid therapy and is not recommended for this purpose. Patients on chronic opioid therapy or with a history of opioid abuse may require higher analgesic doses in the post-operative period than are available from Ionsys; therefore these patients should be evaluated frequently to ensure they are receiving adequate analgesia.
Topical Skin Reactions

Topical skin reactions (erythema, sweating, vesicles, papules/pustules) may occur after removal of Ionsys and are typically limited to the application site area. Reactions typically resolve without treatment. If a severe skin reaction is observed, treat with a topical antiseptic/antibiotic as appropriate.

Respiratory Depression

Fentanyl may cause potentially life-threatening respiratory depression. Consequently, patients with hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored until respiration has stabilized. The use of concomitant CNS-active drugs requires special patient care and observation (see WARNINGS).
Pulmonary Disease

Because potent opioids may cause serious or life-threatening hypoventilation, Ionsys should be administered with caution to patients with pre-existing medical conditions predisposing them to hypoventilation. In such patients, analgesic doses of opioids may further decrease respiratory drive to the point of respiratory failure.
Head Injuries and Increased Intracranial Pressure

Ionsys should not be used in patients who may be particularly susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Opioids may obscure the clinical course of patients with head injury. Ionsys should be used with caution in patients with brain tumors.
Cardiac Disease

Fentanyl may produce bradycardia in some patients. Therefore, Ionsys should be administered with caution to patients with bradyarrhythmias.
Hepatic Disease

Insufficient data are available on the use of Ionsys in patients with impaired hepatic function. Since fentanyl is eliminated by hepatic metabolism, and fentanyl clearance may decrease in patients with hepatic disease, Ionsys should be used with caution in these patients.
Renal Disease

Approximately 10% of administered fentanyl is excreted unchanged by the kidney. Insufficient data are available on the use of IonsysTM in patients with impaired renal function. Ionsys should be used with caution in these patients.
Patient Information

A Patient Instructions for Use sheet is included in the package for Ionsys (see Patient Bedside Information Sheet). Health care professionals are encouraged to review this material with patients.

Patients should be advised not to let anyone else activate the dosing button on the Ionsys system since only the patient knows how much pain he or she is experiencing. Patients

should be cautioned that allowing others to activate the device may result in a potentially fatal overdose. Patients should be instructed not to touch the sticky side of the system and not to touch the gels. Patients should be cautioned that fentanyl is rapidly absorbed by the eyes and mouth, and could be harmful or fatal if absorbed this way. Patients should be advised to inform a health care provider if accidental exposure occurs and to immediately rinse the affected area with copious amounts of water. Soap, alcohol, or other solvents should not be used because they may enhance permeability. Patients should be advised to inform the health care provider of any allergies to fentanyl, cetylpiridinium chloride (e.g. Cepacol), or any components of the Ionsys system. Patients should be advised not to give Ionsys to other people, as it may lead to serious and life-threatening events.

Drug Interactions Central Nervous System Depressants

The concomitant use of other central nervous system depressants, including other opioids, sedatives, hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, or alcoholic beverages, may produce additive depressant effects. Hypoventilation, hypotension, profound sedation, coma, or death may occur. Therefore, use of concomitant CNS depressants requires individual adjustment of dosage of the concomitant medication and observation of a given patient.
Agents Affecting CYP3A4 Isoenzyme System

Fentanyl is metabolized mainly via the cytochrome P450 3A4 enzyme (CYP3A4). Therefore, drug interactions may occur when Ionsys is given concurrently with agents that affect CYP3A4 activity. Coadministration with agents that induce CYP3A4 activity, such as rifampin, carbamazepine, phenytoin, and Saint John's Wort may cause increased clearance of fentanyl and reduce the efficacy of Ionsys. The concomitant use of fentanyl with CYP3A4 inhibitors such as macrolide antibiotics (e.g. erythromycin), azole antifungal agents (e.g. ketoconazole), or protease inhibitors (e.g. ritonavir) may result in a decrease in fentanyl clearance, which could increase or prolong adverse drug effects including serious respiratory depression. In this situation, special patient care and observation are appropriate.
Carcinogenesis, Mutagenesis, and Impairment of Fertility

Studies in animals to evaluate the carcinogenic potential of fentanyl HCl have not been conducted. There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in-vitro assays. The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4

mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.2 times the maximum available daily human dose on a mg/m2 basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.
Pregnancy Teratogenic EffectsPregnancy Category C

No epidemiologic studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported. The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit models. Published literature reports that administration of fentanyl (0, 10, 100, or 500 mcg/kg/day) to pregnant female Sprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of teratogenicity (the high dose is approximately 1.5 times the maximum available daily human dose on a mg/m2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female rats from gestation day 6 to 18 suggested evidence of embryotoxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted. Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately 3 times the maximum achievable human daily dose on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women. Ionsys should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects

Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day 6 of pregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor

eruption and eye opening) and transient behavioral development (decreased locomotor activity at day 28 which recovered by day 50). The mid-dose and the high-dose are 0.3 and 1.5 times the maximum available daily human dose on a mg/m2 basis.
Labor and Delivery

Fentanyl readily passes across the placenta to the fetus; therefore Ionsys is not recommended for analgesia during labor and delivery.
Nursing Mothers

Fentanyl is excreted in human milk; therefore Ionsys is not recommended for use in nursing women because of the possibility of sedation and/or respiratory depression in their infants.
Pediatric Use

Not for pediatric use. The efficacy and safety of Ionsys have not been adequately studied in pediatric patients under 18 years of age. Preliminary pediatric studies using iontophoretically-delivered fentanyl at a lower dose suggested that pediatric patients were more vulnerable to application site reactions, which were more severe than in adults.
Geriatric Use

Ionsys 40 mcg has been studied in 499 patients 65 years or older; 174 of whom were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, the incidence of the following events was slightly higher ( 1%) in patients 65 years compared with patients who were 18 to 64 years of age: hypotension (4 % versus 3%), confusion (2% versus <1%), hypokalemia (3% versus 1%), hypoxia (3% versus 2%), and hypoventilation (2% versus <1%). In a pharmacokinetic study of Ionsys conducted in 63 healthy volunteers (25 subjects older than 65 years), age did not significantly affect the extent of drug absorption. Literature suggests that the clearance of fentanyl may be reduced and the terminal half-life prolonged in the elderly (see PRECAUTIONS).

Adverse Reactions
In controlled and uncontrolled studies, the safety of Ionsys 40 mcg was evaluated in a total of 2114 patients with acute postoperative pain requiring opioid analgesia. The most common adverse events (2%) in the placebo-controlled studies, regardless of relationship to study medication, are listed in Table 5.
Table 5 Adverse Events with Incidence 2% in Placebo-controlled Studies 1, 2, and 3 (N=791; 24 Hour Duration), Regardless of Relationship to Study Medication

* NOTE: Patients reported as having Nausea and vomiting are included in Nausea and Vomiting in Table 5.
Adverse Event Ionsys (n=475) Placebo (n=316)

Body as a Whole Headache Fever Back Pain Cardiovascular Hypotension Digestive* Nausea Vomiting Hemic and Lymphatic Anemia Nervous system Insomnia Dizziness Skin system Application site reaction- Erythema Pruritus Urogenital Urinary retention 3% <1% 14% 6% 2% <1% 3% 3% 5% 1% 3% <1 % 39 % 12 % 22 % 6% 2% <1 % 9% 9% 2% 7% 10 % 3%

Adverse Events Reported in All Studies in Patients Treated With Ionsys (40 mcg/dose: n= 2114 including 3 Placebo-Controlled Trials and 4 Active Comparator Trials vs. IV PCA morphine)

The most common (>10%) adverse events reported regardless of relationship to Ionsys use were nausea, vomiting, application site reaction-erythema, fever, and headache. Other adverse events reported for Ionsys were: (** indicates 1 to <10%, * indicates between 0.1 to <1%). Body as a whole: abdominal pain**, back pain**, extremity pain**, pain**, injection site reaction*, chills*, internal postoperative bleeding*, chest pain*, infection*, injection site edema*, injection site pain*, immune system disorder*, abdomen enlarged*, asthenia*, neck pain*, abscess*, and hypothermia*, Cardiovascular System: hypotension**, tachycardia**, hypertension**, syncope*, postural hypotension*, pulmonary embolus*, atrial fibrillation*, bradycardia*, migraine*, myocardial infarct*, vasodilation*, hemorrhage*, deep thrombophlebitis*, bigeminy*, and arrhythmia*, Digestive System: constipation**, flatulence**, dyspepsia**, ileus**, gastrointestinal disorder*, dry mouth*, diarrhea*, and gastrointestinal hemorrhage*, Hemic and Lymphatic System: anemia**, and leukocytosis*, and Metabolic and Nutritional System: hypokalemia**, peripheral edema*, hypomagnesemia*, hypocalcemia*, hyponatremia*, hyperglycemia*, healing abnormal*, hypoglycemia*, hypophosphatemia*, edema*, and dehydration*, Musculoskeletal System: leg cramps* and myalgia*, Nervous System: dizziness**, insomnia**, anxiety**, hypertonia**, somnolence**, confusion*, paresthesia*, hypesthesia*, nervousness*, agitation*, abnormal dreams*, and tremor*, Respiratory System: hypoxia**, pharyngitis**, hypoventilation*, dyspnea*, apnea*, cough increased*, lung disorder*, asthma*, hiccup*, pneumonia*, atelectasis*, upper respiratory tract infection*, rhinitis*, sinusitis*, and hyperventilation*, Skin System: pruritus**, application site reaction (ASR)-itching**, ASRvesicles**, ASR-edema**, ASR-other**, sweating**, wound site oozing/bleeding**, wound site inflammation/erythema*, rash*, ASR-dry and flaky*, ASR-papules/pustules*, vesiculobullous rash*, ASR-pain*, ASR-burning*, Special Senses: abnormal vision-blurred vision*, and ear pain*, Urogenital System: urinary retention**, urination impaired*, oliguria*, urogenital disorder*, hematuria*, urinary tract infection*, urinary urgency*, and dysuria*. The level of current (62 microA/cm2) provided by Ionsys is generally imperceptible to the patient. Scheduled observation of the skin approximately 24 hours after system removal was included in several studies. Some redness at the skin sites was observed in approximately 60% of patients at this observation. The skin findings included erythema, edema, and papules. The majority of these events were categorized as mild. Two patients were noted to have hyperpigmentation lasting 2-3 weeks at the application site. Three patients from another study noted a rectangular mark at the application site, which persisted for up to 3 months after study completion.
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Drug Abuse and Dependence

Controlled Substance

Ionsys contains fentanyl, a Schedule II controlled substance.

Abuse

Ionsys contains a high concentration of a potent Schedule II controlled opioid agonist, fentanyl. Schedule II opioid substances, which include fentanyl, morphine, oxycodone, oxymorphone, hydromorphone, and methadone, have the highest potential for abuse. These drugs also have a risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high drug content and concentrated formulation of fentanyl in Ionsys may be a particular target for abuse and diversion and may add to the risk of adverse outcomes from abuse. After the maximum dosage administration, a significant amount of fentanyl remains in the device. Access to abusable drugs such as Ionsys presents a risk for abuse and diversion in the health care community. Implementation of effective accounting procedures in addition to routine procedures for handling controlled substances may minimize these risks.
Dependence

Tolerance and physical and psychological dependence may develop upon repeated administration of opioids. Iatrogenic addiction following opioid administration is relatively rare. Physicians should not let concerns of physical dependence deter them from using adequate amounts of opioids in the management of acute post-operative pain when such use is indicated.

Overdosage
Clinical Presentation

The manifestations of fentanyl overdosage are an extension of its pharmacologic actions, with the most serious effect being respiratory depression.

Treatment

For the management of respiratory depression, immediate countermeasures include removing Ionsys and discontinuing administration of any other opiates until the episode has resolved, as well as physically or verbally stimulating the patient. If needed, these actions can be followed by administration of a specific narcotic antagonist such as naloxone. Reversal of the narcotic effect may result in acute onset of pain and the release of catecholamines. If the clinical situation warrants, ensure a patent airway is established and maintained, administer oxygen and assist or control respiration as indicated, and use an oropharyngeal airway or endotracheal tube if necessary. Adequate body temperature and fluid intake should be maintained. If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy.

Ionsys Dosage and Administration

Patients should be titrated to comfort before initiating Ionsys. Patients must have access to supplemental analgesia. Ionsys should be applied to intact, non-irritated and non-irradiated skin on the chest or upper outer arm. Ionsys provides 40 mcg dose of fentanyl per activation on-demand. It is important to instruct patients how to operate Ionsys to self-administer doses of fentanyl as needed to manage their acute, short-term, postoperative pain. Only the patient should administer doses from Ionsys. Each on-demand dose is delivered over a 10-minute period. To initiate administration of a fentanyl dose, the patient must press the button twice firmly within 3 seconds. An audible tone (beep) indicates the start of delivery of each dose; the red light remains on throughout the 10-minute dosing period. Patients on chronic opioid therapy or with a history of opioid abuse may require higher analgesic doses in the post-operative period than are available from Ionsys. Therefore, these patients should be evaluated frequently to ensure they are receiving adequate analgesia.

A maximum of six 40-mcg doses per hour can be administered by Ionsys. The maximum amount of fentanyl that can be administered from a single Ionsys system over 24 hours is 3.2 mg (eighty 40-mcg doses). Each Ionsys system operates for 24 hours or until 80 doses have been administered, whichever occurs first. Up to three consecutive Ionsys systems may be used sequentially, each applied to a different skin site for a maximum of 72 hours of therapy for acute, short-term, postoperative pain.

Ionsys Testing Instructions for the Pharmacist or Other Health Care Professional (To be Performed Prior to Dispensing)

Each Ionsys should be tested before it is dispensed to a patient. The following functionality test should be performed by the pharmacist or pharmacy technician with Ionsys still in its sealed pouch:
1. 2. 3. 4. 5. Hold the unopened foil pouch that contains the Ionsys system Ionsys button side is indicated on the pouch label Run a finger along the system until you feel the recessed button on one end Firmly press and release the button twice within 3 seconds (i.e., double-CLICK) Listen for a single audible tone (beep), confirming that the Ionsys system is functional and can be dispensed. If no tone is heard, the system is not functioning and should not be dispensed. 6. The pharmacist should sign the front of pouch after performing a functionality test. The sticker on the back is intended for use by the registered Nurse (RN).

After a single audio tone is emitted based on this functionality test, a normally operating Ionsys system will also beep for 15 seconds after 4 minutes. This indicates that Ionsys is not in contact with the skin. Therefore, a functional system is confirmed by a single beep and/or 15 seconds of beeps after pressing the button. If a nurse or other health care professional performs the functionality test, and the system is applied to a patient within 4 minutes of having completed the test, the system will deliver the remainder of the 10-minute dose. For example, if the system is applied to the patient 3 minutes after the completion of the functionality test (i.e. when single beep is emitted), the system will deliver a 7-minute dose for this dose only. If a system is applied after the series of beeps is completed at 4 minutes, the system will deliver a 10-minute dose upon each activation. If neither the single beep emitted upon double-pressing the dosing button nor the 15 second beeping after 4 minutes are heard, the system may be nonfunctional (see Troubleshooting.) For questions about Ionsys, including product returns, please call Ortho-McNeil, Inc at 1-800-526-7736 . Any nonfunctional system returned to the manufacturer should be returned in its intact package. Do not open the pouch of a non-functional system and do not dispense it to a patient. No drug is delivered from the system unless Ionsys is applied to the skin. Therefore, 80 doses and 24 hours of use are still available after the functionality test is performed.
Method of Application

Ionsys should be applied to intact, non-irritated, and non-irradiated skin on the chest or upper outer arm. Ionsys should not be placed on abnormal skin sites, such as scars, burns, tattoos, etc. Any excessive hair at the application site should be clipped (not shaved) before system application. Wipe the application site with a standard alcohol swab and allow the skin to dry completely before applying Ionsys. Do not use any soaps, oils, lotions, or any other agents that might irritate the skin or alter its absorption characteristics.

The sticker on the back of the pouch is intended for use by the registered nurse (RN). Fields on the sticker are provided for the nurse to write in the time and date Ionsys is applied to the patient. This sticker should be transferred from the pouch label to the Ionsys system that will be applied to the patient, in order to provide information to the next nurse on staff regarding when the 24-hour clock on Ionsys will expire. To open the pouch containing Ionsys, use scissors to cut along the dotted line of the pouch.

Remove and discard only the clear plastic liner covering the adhesive. Take care not to pull on the red tab while removing the clear plastic liner when preparing to apply Ionsys to the patient. The red tab is only to be used when separating the Ionsys system for disposal. (See disposal)

Press Ionsys firmly in place, with the sticky side down, on the skin for at least 15 seconds. Press with your fingers around the outer edges to be sure the system sticks to the skin.

Occasionally, Ionsys may loosen; if this occurs a non-allergenic tape may be used to be sure all of the system's edges make complete contact with the skin. Take care not to tape over the button or the red light. Each Ionsys may be used for 24 hours from completion of the first on-demand dose or until 80 doses have been administered, whichever comes first. After the 24 hours have elapsed, or 80 doses have been delivered, Ionsys is deactivated and cannot deliver any additional doses i.e. if the patient tries to initiate a dose, the system will not beep and the red LED will not

light up continuously. At this time the red LED will continue to flash indicating the approximate number of doses delivered to the patient up until the time the system was deactivated. The LED will continue to flash until the battery in the system is depleted. If additional opioid analgesia is required, a new system should be applied to a different skin site after removal and disposal of the previous system.
Dose Delivery

A recessed button and red light are located on the top housing of Ionsys. To initiate a fentanyl dose, the patient should press the button twice within 3 seconds. An audible tone (beep) indicates the start of delivery of each dose; the red light remains on throughout the 10minute dosing interval. The next dose cannot begin until the previous 10-minute delivery cycle is complete. Pressing the button during delivery of a dose will not result in additional drug being administered. The red light turns off after each 10-minute dose has been delivered.

A healthcare professional should observe the first dose administered to ensure that the patient understands how to operate Ionsys and that the system is working properly.
Determining Approximate Number of Doses Delivered

Between doses, the red light will flash in one-second pulses to indicate the approximate number of doses that have been administered up to the present time. Each one-second flash of light indicates administration of up to five doses. Thus, a single one-second flash of light represents 1 to 5 doses; two flashes represent 6 to 10 doses; three flashes represent 11 to 15 doses; and so on up to 16 flashes which represent 76 to 80 doses delivered. The system may also be queried during delivery of an on-demand dose, by a single press of the button. The red light will flash as outlined above to indicate the approximate number of on-demand doses that have been delivered up to the time of the query. This query will not influence dose delivery.
Determining Approximate Dose of Fentanyl Delivered Based on the Number of Red Light Flashes No. of light flashes No. of fentanyl doses delivered 1-5 6-10 11-15 16-20 Range (mcg) of fentanyl delivered 40-200 240-400 440-600 640-800

1 2 3 4

Determining Approximate Dose of Fentanyl Delivered Based on the Number of Red Light Flashes No. of light flashes No. of fentanyl doses delivered 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 Range (mcg) of fentanyl delivered 840-1,000 1040-1200 1240-1400 1440-1600 1640-1800 1840-2000 2040-2200 2240-2400 2440-2600 2640-2800 2840-3000 3040-3200

5 6 7 8 9 10 11 12 13 14 15 16 Removal

Ionsys may be removed at any time. However, once a system has been removed, the same system should not be reapplied.

At the end of 24 hours of use, or after 80 doses have been delivered, the Ionsys system will deactivate and should be removed from the patient's skin. Using gloves, remove Ionsys by gently lifting the red tab and loosening the system from the skin application site. Ensure both hydrogels remain with the removed Ionsys system. If the hydrogel becomes separated from the Ionsys system during removal, use gloves or tweezers to remove the hydrogel from the skin and properly dispose of in accordance with state and federal regulations for controlled substances. If the patient requires additional pain relief, a new Ionsys system should be applied. In this case, Ionsys should be applied to a new skin site on the upper outer arm or chest.

Take care not to touch the exposed hydrogel compartments or the adhesive. If a hydrogel drug reservoir is touched accidentally, rinse the area thoroughly with water (do not use soap).
Disposal

Contact with the hydrogels contained in Ionsys can be harmful to humans and animals. Medical staff should handle the removed system carefully and only by the sides and top housing. Disposal should be in accordance with state and federal regulations for controlled substances. The used bottom housing of Ionsys contains a significant amount of fentanyl that could be harmful or fatal if ingested and which could be diverted for abuse. To dispose of a used Ionsys:
1. Using gloves, pull the red tab to separate the bottom housing from the top housing.

2. Fold the bottom hydrogel-containing housing in half with the sticky side facing in.

3. Dispose of the folded over bottom housing, containing the residual fentanyl, by flushing this piece down the toilet. This step should be witnessed by a second health care provider. The used bottom housing of Ionsys contains fentanyl that could be harmful or fatal if ingested. 4. Dispose of top housing, containing electronics, according to hospital procedures for batterycontaining waste. 5. If the hydrogel accidentally contacts the skin, rinse the affected area thoroughly with water (do not use soap). Contact with the fentanyl hydrogel contained in Ionsys can be harmful to humans and animals. Oral ingestion or contact of the hydrogels with mucous membranes may cause serious illness or death. Do not allow hydrogel to touch mouth. Troubleshooting

Ionsys is designed to deliver each on-demand dose of fentanyl over approximately 10 minutes. Please refer to the Normal System Feedback table below which illustrates normal audio and visual feedback from the Ionsys system, both during the in-pouch functionality testing that is performed before the system is dispensed to a patient, and during patient use.
Normal System Feedback Mode Ionsys functionality testing (performed prior to dispensing Audio Feedback Visual Feedback

to patient): 1. With the Ionsys system in its unopened pouch, run a finger along the system until the recessed dosing button is felt (pouch label indicates the side on which the button will be located) 2. Firmly press and release the button twice within 3 seconds Immediately after step 2 is performed, the system will emit a single beep, indicating a functional system. Approximately four minutes later, the system will also emit a series of short beeps (15 seconds duration). This is normal and does not affect the functionality or life of the product once applied to the patient. None (system is in opaque foil pouch). Note that if this test were performed with Ionsys outside of the pouch and off the patient's body, the red LED would illuminate for 4 minutes and then turn off at the time the 15 seconds beeping starts.

During and After Patient Use Initiate administration of a dose A single audio tone (beep) The red light remains solidly by pressing the button twice indicates the start of delivery of illuminated throughout each 10firmly within 3 seconds. each dose. minute dosing period. Advise Patient that when None. system is flashing, he or she can self-administer another dose of fentanyl from the system as needed for pain relief At any time within 24 hours of initiation of first dose from system, and < 80 doses have been delivered, system displays flashing red light to give an approximation of the fentanyl doses that have been administered. Each series of flashes, followed by a 2 second pause, will repeat until the patient administers the next dose. Each flash of light represents administration of 1-5 fentanyl doses (40 mcg each) Displays flashing red light after 24 hours have elapsed from time of initiation of the first dose from system, OR all 80 doses have been delivered. System is deactivated and a new system must be applied to a new skin site if needed

System deactivates after 24 None. hours have elapsed from time of first dose administered, or if all 80 doses have been used. You may determine the number of doses administered by counting the number of flashes during one series. Each pulse of light represents the administration of 1-5 fentanyl

doses (40 mcg each)

If a system does not appear to function immediately, wait 4 minutes and firmly press and release the button twice within 3 seconds (i.e., double-press). A single audio beep will be emitted immediately, confirming that the Ionsys system is functional. If a system is not functioning properly, instruct the patient to call a staff member to observe the next time he/she initiates a dose. Then monitor both the illumination of the red light and any error messages (beeps) that may be provided by the system. Refer to the Error Messages chart below for possible problems and appropriate course of action. Error messages provide information about problems that may occur during operation of Ionsys. These messages are in the form of alarms consisting of a series of audible signals or beeps as follows:
Error Messages Error Message/Feedback Probable Cause Action Ensure good contact is made between the gels and the skin. Attempt to restart system (up to 3 times). If required, a new system should be applied to a new skin site. Remove system from patient. System cannot be restarted. Apply new system to a new site.

Emits a 15 second series of Decreased fentanyl delivery. beeps (this short series of beeps Could be caused by poor contact between the system repeats 8 times then stops). and the skin or due to high skin resistance.

Emits a continuous series of beeps that repeat until the battery is depleted (i.e. beeps cannot be shut off).

Ionsys placed on compromised skin site, increased output current detected, or low battery voltage. Depleted battery or nonfunctional system.

No single beep emitted, and no solid red light illuminated upon dose activation. Red light is not flashing. Discontinuation of Ionsys

Remove system, and if required, a new system should be applied to a new skin site.

To convert patients to another opioid or other analgesic, remove Ionsys and titrate the dose of the new analgesic, based upon the patient's report of pain, until adequate analgesia has been obtained, using caution due to the fact that serum fentanyl concentration will decrease slowly following removal of the system (See Figure 1b; WARNINGS). Following cessation of Ionsys treatment in clinical trials, patients were typically administered oral analgesics; a small percentage of patients received parenteral opioids.

How is Ionsys Supplied

Ionsys is provided as a disposable system providing up to 80 doses (40 mcg each) of fentanyl. Each Ionsys is individually packaged in a child-resistant foil pouch. There are five packages per carton. NDC # 0062-7900-01 (single Ionsys system in foil pouch) NDC # 0062-7900-05 (carton of 5 Ionsys systems)
Storage and Handling

Accidental ingestion of the fentanyl hydrogel or contact of the hydrogel with mucous membranes could lead to the absorption of a potentially fatal dose of fentanyl. Therefore, the hydrogels should not come into contact with fingers or mouth. Avoid direct contact with the fentanyl hydrogel and the adhesive surface during system application and removal. If the hydrogel from the drug reservoir accidentally contacts the skin, the affected area should be rinsed thoroughly with water. Do not use soap, alcohol, or other solvents to remove the hydrogel because they may enhance the drug's ability to penetrate the skin. Ionsys should be stored at 25C (77F); excursions permitted to 15 30C (59-86F). Apply to the skin immediately after removal from the individually sealed package. Do not use if the foil pouch has been broken. For transdermal use only. For questions about Ionsys, including product returns please call Ortho-McNeil, Inc. Medical Communications Contact Center at Rx only Marketed by: Ortho-McNeil, Inc. Raritan, NJ 08869 Manufactured by: ALZA Corporation Mountain View, CA 94043 An ALZA E-TRANS Technology Product Revised August 2006 (0016720-2)
PATIENT INFORMATION

1-800-526-7736 .

Patient Bedside Information Sheet Ionsys (eye-AHN-sis) (fentanyl iontophoretic transdermal system) Patient-activated CII

40 mcg per activation IMPORTANT: Never leave the hospital with an Ionsys system on your skin. Ionsys is not for home use. Ionsys can cause life-threatening breathing problems or death if it is used the wrong way.

What is Ionsys? Ionsys:

contains the prescription medicine, fentanyl. Fentanyl is a very strong narcotic pain medicine (opioid). is only for hospitalized adults with short-term, moderate to severe pain after surgery is a patient-controlled medicine device (system) that sticks to the skin

Ionsys is not:

for use at home for patients who cannot understand or use Ionsys without help for patients who are allergic to: o fentanyl o Cepacol (cetylpiridinum chloride)

Your nurse or doctor:

will tell you about Ionsys and teach you how to use it before your surgery will put an Ionsys system on your skin (on your upper outer arm or chest) after your surgery will control pain from your surgery with other pain medicines until you are awake enough to use Ionsys will monitor you for side effects from Ionsys. Ionsys can cause life-threatening breathing problems because it contains a very strong narcotic pain medicine. will replace your Ionsys system as needed will remove your Ionsys system before you leave the hospital

Using Ionsys:

You can push the Ionsys dosing button when needed to control your pain or just before you do an activity that may increase your pain such as physical therapy or getting out of bed. To get a dose of pain medicine from Ionsys, double-click the dosing button (twice within 3 seconds). When you push the dosing button you will hear a single beep and the red light above the dosing button will light up. This red light will remain lit for the 10 minutes it takes to deliver a dose of fentanyl. You cannot give yourself another dose of medicine from Ionsys while the red light is lit. When Ionsys is finished delivering a dose, the red light will start flashing. This means you can give yourself more pain medicine, if needed, by double clicking the dosing button. The flashes also tell your doctor and nurse about how many doses of medicine from Ionsys that you have taken. Let your doctor or nurse know if you have problems using Ionsys. They will check your Ionsys system to make sure it is working.

Never:

Never let anyone else press the Ionsys dosing button for you. Never touch the sticky side of Ionsys if it falls off of your skin. Let your nurse or doctor know right away if an Ionsys system has come off of your skin. Wash your hands right away if you accidentally touch the sticky side of Ionsys and let your doctor or nurse know right away. Never remove or replace an Ionsys system yourself. Never leave the hospital with an Ionsys system on your skin. Make sure your nurse or doctor removes your Ionsys system before you leave the hospital

Ionsys fentanyl hydrochloride patch, extended release, electrically controlled Product Information Product Type Route of Administration HUMAN PRESCRIPTION DRUG LABEL TRANSDERMAL Item Code (Source) DEA Schedule NDC:00627900 CII

Active Ingredient/Active Moiety Ingredient Name fentanyl hydrochloride (fentanyl) Inactive Ingredients Ingredient Name Polacrilin Strength Basis of Strength fentanyl Strength 10.8 mg

Water Sodium Hydroxide Polyvinyl Alcohol Sodium Chloride Sodium Citrate Citric Acid Cetylpyridinium Chloride Packaging # Item Code 1 NDC:0062-790001 NDC:0062-790005 Package Description 1 PATCH, EXTENDED RELEASE, ELECTRICALLY CONTROLLED (1 PATCH) in 1 POUCH 5 PATCH, EXTENDED RELEASE, ELECTRICALLY CONTROLLED (5 PATCH) in 1 CARTON

Labeler - Ortho-McNeil, Inc. Revised: 07/2007

Ortho-McNeil, Inc http://www.drugs.com/cdi/numorphan.html