Zevalin

ibritumomab tiuxetan

Dosage Form: injection
FULL PRESCRIBING INFORMATION

WARNING: SERIOUS INFUSION REACTIONS, PROLONGED AND SEVERE CYTOPENIAS, and SEVERE CUTANEOUS AND MUCOCUTANEOUS REACTIONS

Serious Infusion Reactions: Deaths have occurred within 24 hours of rituximab infusion, an essential component of the Zevalin therapeutic regimen. These fatalities were associated with hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Most (80%) fatalities occurred with the first rituximab infusion [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Discontinue rituximab and Y-90 Zevalin infusions in patients who develop severe infusion reactions.

Prolonged and Severe Cytopenias: Y-90 Zevalin administration results in severe and prolonged cytopenias in most patients. Do not administer Y-90 Zevalin to patients with ≥ 25% lymphoma marrow involvement and/or impaired bone marrow reserve [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Severe Cutaneous and Mucocutaneous Reactions: Severe cutaneous and mucocutaneous reactions, some fatal, can occur with the Zevalin therapeutic regimen. Discontinue rituximab and Y-90 Zevalin infusions in patients experiencing severe cutaneous or mucocutaneous reactions [see Warnings and Precautions (5.3) and Adverse Reactions (6.3)].

Dosing: The dose of Y-90 Zevalin should not exceed 32.0 mCi (1184 MBq) [see Dosage and Administration (2.2)].

Indications and Usage for Zevalin

Relapsed or Refractory, Low-grade or Follicular NHL 

Zevalin is indicated for the treatment of relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL).

Previously Untreated Follicular NHL 

Zevalin is indicated for the treatment of previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy.

Zevalin Dosage and Administration

Recommended Dosing Schedule:

• Administer the Zevalin therapeutic regimen as outlined in Section 2.1.


• Initiate the Zevalin therapeutic regimen following recovery of platelet counts to ≥150,000/mm3 at least 6 weeks, but no more than 12 weeks, following the last dose of first-line chemotherapy.

Overview of Dosing Schedule

Zevalin Therapeutic Regimen Dosage and Administration

Day 1:

• Premedicate with acetaminophen 650 mg orally and diphenhydramine 50 mg orally prior to rituximab infusion.


• Administer rituximab 250 mg/m2 intravenously at an initial rate of 50 mg/hr. In the absence of infusion reactions, escalate the infusion rate in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Do not mix or dilute rituximab with other drugs.


• Immediately stop the rituximab infusion for serious infusion reactions and discontinue the Zevalin therapeutic regimen [see Boxed Warning and Warnings and Precautions (5.1)].


• Temporarily slow or interrupt the rituximab infusion for less severe infusion reactions. If symptoms improve, continue the infusion at one-half the previous rate.

Day 7, 8 or 9:

• Premedicate with acetaminophen 650 mg orally and diphenhydramine 50 mg orally prior to rituximab infusion.


• Administer rituximab 250 mg/m2 intravenously at an initial rate of 100 mg/hr. Increase rate by 100 mg/hr increments at 30 minute intervals, to a maximum of 400 mg/hr, as tolerated. If infusion reactions occurred during rituximab infusion on Day 1 of treatment, administer rituximab at an initial rate of 50 mg/hr and escalate the infusion rate in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.


• Administer Y-90 Zevalin injection through a free flowing intravenous line within 4 hours following completion of rituximab infusion. Use a 0.22 micron low-protein-binding in-line filter between the syringe and the infusion port. After injection, flush the line with at least 10 mL of normal saline.
  
  • If platelet count ≥ 150,000/mm3, administer Y-90 Zevalin over 10 minutes as an intravenous injection at a dose of Y-90 0.4 mCi per kg (14.8 MBq per kg) actual body weight.
  
  
  • If platelet count ≥ 100,000 but ≤149,000/mm3, in relapsed or refractory patients, administer Y-90 Zevalin over 10 minutes as an intravenous injection at a dose of Y-90 0.3 mCi per kg (11.1 MBq per kg) actual body weight.
  
  
  • Do not administer more than 32 mCi (1184 MBq) Y-90 Zevalin dose regardless of the patient’s body weight.
  
  


• Monitor patients closely for evidence of extravasation during the injection of Y-90 Zevalin. Immediately stop infusion and restart in another limb if any signs or symptoms of extravasation occur [see Warnings and Precautions (5.7)].

Directions for Preparation of Radiolabeled Y-90 Zevalin Doses

A clearly-labeled kit is required for preparation of Yttrium-90 (Y-90) Zevalin. Follow the detailed instructions for the preparation of radiolabeled Zevalin [see Dosage and Administration (2.4)].

Required materials not supplied in the kit:

1. Yttrium-90 Chloride Sterile Solution


2. Three sterile 1 mL plastic syringes


3. One sterile 3 mL plastic syringe


4. Two sterile 10 mL plastic syringes with 18-20 G needles


5. ITLC silica gel strips


6. 0.9% Sodium Chloride aqueous solution for the chromatography solvent


7. Developing chamber for chromatography


8. Suitable radioactivity counting apparatus


9. Filter, 0.22 micrometer, low-protein-binding


10. Appropriate acrylic shielding for reaction vial and syringe for Y-90

Method:

1. Allow contents of the refrigerated Y-90 Zevalin kit (Zevalin vial, 50 mM sodium acetate vial, and formulation buffer vial) to reach room temperature.


2. Place the empty reaction vial in an appropriate acrylic shield.


3. Determine the amount of each component needed:
   
   1. Calculate volume of Y-90 Chloride equivalent to 40 mCi based on the activity concentration of the Y-90 Chloride stock.
   
   
   2. The volume of 50 mM Sodium Acetate solution needed is 1.2 times the volume of Y-90 Chloride solution determined in step 3.a, above.
   
   
   3. Calculate the volume of formulation buffer needed to bring the reaction vial contents to a final volume of 10 mL.
   
   


4. Transfer the calculated volume of 50 mM Sodium Acetate to the empty reaction vial. Coat the entire inner surface of the reaction vial by gentle inversion or rolling.


5. Transfer 40 mCi of Y-90 Chloride to the reaction vial using an acrylic shielded syringe. Mix the two solutions by gentle inversion or rolling.


6. Transfer 1.3 mL of Zevalin (ibritumomab tiuxetan) to the reaction vial. Do not shake or agitate the vial contents.


7. Allow the labeling reaction to proceed at room temperature for 5 minutes. A shorter or longer reaction time may adversely alter the final labeled product.


8. Immediately after the 5-minute incubation period, transfer the calculated volume of formulation buffer from step 3.c. to the reaction vial. Gently add the formulation buffer down the side of the reaction vial. If necessary, withdraw an equal volume of air to normalize pressure.


9. Measure the final product for total activity using a radioactivity calibration system suitable for the measurement of Y-90.


10. Using the supplied labels, record the date and time of preparation, the total activity and volume, and the date and time of expiration, and affix these labels to the shielded reaction vial container.


11. Patient Dose: Calculate the volume required for a Y-90 Zevalin dose [see Dosage and Administration (2.2)].  Withdraw the required volume from the reaction vial. Assay the syringe in the dose calibrator suitable for the measurement of Y-90. The measured dose must be within 10% of the prescribed dose of Y-90 Zevalin and must not exceed 32 mCi (1184 MBq). Using the supplied labels, record the patient identifier, total activity and volume and the date and time of expiration, and affix these labels to the syringe and shielded unit dose container.


12. Determine Radiochemical Purity [see Dosage and Administration (2.4)].


13. Store Yttrium-90 Zevalin at 2-8°C (36-46°F) until use and administer within 8 hours of radiolabeling. Immediately prior to administration, assay the syringe and contents using a radioactivity calibration system suitable for the measurement of Y-90.

Procedure for Determining Radiochemical Purity

Use the following procedures for radiolabeling Y-90 Zevalin:

1. Place a small drop of Y-90 Zevalin at the origin of an ITLC silica gel strip.


2. Place the ITLC silica gel strip into a chromatography chamber with the origin at the bottom and the solvent front at the top. Allow the solvent (0.9% NaCl) to migrate at least 5 cm from the bottom of the strip. Remove the strip from the chamber and cut the strip in half. Count each half of the ITLC silica gel strip for one minute (CPM) with a suitable counting apparatus.


3. Calculate the percent RCP as follows:
   
   
   


4. Repeat the ITLC procedure if the radiochemical purity is <95%. If repeat testing confirms that radiochemical purity is <95%, do not administer the Y-90 Zevalin dose.

Radiation Dosimetry

During clinical trials with Zevalin, estimations of radiation-absorbed doses for Y-90 Zevalin were performed using sequential whole body images and the MIRDOSE 3 software program. The estimated radiation absorbed doses to organs and marrow from a course of the Zevalin therapeutic regimen are summarized in Table 1. Absorbed dose estimates for the lower large intestine, upper large intestine, and small intestine have been modified from the standard MIRDOSE 3 output to account for the assumption that activity is within the intestine wall rather than the intestine contents.

Table 1. Estimated Radiation Absorbed Doses from Y-90 Zevalin

* Organ region of interest † Sacrum region of interest ‡ Whole body region of interest
Organ	Y-90 Zevalin cGy /mCi (mGy/MBq)
	Median	Range
Spleen*	34.78 (9.4)	6.66 - 74.00 (1.8 - 20.0)
Liver*	17.76 (4.8)	10.73 - 29.97 (2.9 - 8.1)
Lower Large Intestinal Wall*	17.39 (4.7)	11.47 - 30.34 (3.1 - 8.2)
Upper Large Intestinal Wall*	13.32 (3.6)	7.40 - 24.79 (2.0 - 6.7)
Heart Wall*	10.73 (2.9)	5.55 - 11.84 (1.5 - 3.2)
Lungs*	7.4 (2)	4.44 - 12.58 (1.2 -3.4)
Testes*	5.55 (1.5)	3.70 - 15.91 (1.0 - 4.3)
Small Intestine*	5.18 (1.4)	2.96 - 7.77 (0.8 - 2.1)
Red Marrow†	4.81 (1.3)	2.22 - 6.66 (0.6 - 1.8)
Urinary Bladder Wall‡	3.33 (0.9)	2.59 - 4.81 (0.7 - 1.3)
Bone Surfaces†	3.33 (0.9)	1.85 - 4.44 (0.5 - 1.2)
Total Body‡	1.85 (0.5)	1.48 - 2.59 (0.4 - 0.7)
Ovaries‡	1.48 (0.4)	1.11 - 1.85 (0.3 - 0.5)
Uterus‡	1.48 (0.4)	1.11 - 1.85 (0.3 - 0.5)
Adrenals‡	1.11 (0.3)	0.74 - 1.85 (0.2 - 0.5)
Brain‡	1.11 (0.3)	0.74 - 1.85 (0.2 - 0.5)
Breasts‡	1.11 (0.3)	0.74 - 1.85 (0.2 - 0.5)
Gallbladder Wall‡	1.11 (0.3)	0.74 - 1.85 (0.2 - 0.5)
Muscle‡	1.11 (0.3)	0.74 - 1.85 (0.2 - 0.5)
Pancreas‡	1.11 (0.3)	0.74 - 1.85 (0.2 - 0.5)
Skin‡	1.11 (0.3)	0.74 - 1.85 (0.2 - 0.5)
Stomach‡	1.11 (0.3)	0.74 - 1.85 (0.2 - 0.5)
Thymus‡	1.11 (0.3)	0.74 - 1.85 (0.2 - 0.5)
Thyroid‡	1.11 (0.3)	0.74 - 1.85 (0.2 - 0.5)
Kidneys*	0.37 (0.1)	0.00 - 1.11 (0.0 - 0.3)

Dosage Forms and Strengths

3.2 mg ibritumomab tiuxetan per 2 mL, single-use vial.

Contraindications

None.

Warnings and Precautions

Serious Infusion Reactions

See also prescribing information for rituximab.

Rituximab, alone or as a component of the Zevalin therapeutic regimen, can cause severe, including fatal, infusion reactions. These reactions typically occur during the first rituximab infusion with time to onset of 30 to 120 minutes. Signs and symptoms of severe infusion reactions may include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock. Temporarily slow or interrupt the rituximab infusion for less severe infusion reactions. Immediately discontinue rituximab and Y-90 Zevalin administration for severe infusion reactions [see Boxed Warning and Dosage and Administration (2.2)].

Prolonged and Severe Cytopenias

Cytopenias with delayed onset and prolonged duration, some complicated by hemorrhage and severe infection, are the most common severe adverse reactions of the Zevalin therapeutic regimen. When used according to recommended doses, the incidences of severe thrombocytopenia and neutropenia are greater in patients with mild baseline thrombocytopenia (100,000 to 149,000 /mm3) compared to those with normal pretreatment platelet counts. Severe cytopenias persisting more than 12 weeks following administration can occur [see Boxed Warning and Adverse Reactions (6.1)].

Do not administer the Zevalin therapeutic regimen to patients with ≥ 25% lymphoma marrow involvement and/or impaired bone marrow reserve. Monitor patients for cytopenias and their complications (e.g., febrile neutropenia, hemorrhage) for up to 3 months after use of the Zevalin therapeutic regimen. Avoid using drugs which interfere with platelet function or coagulation following the Zevalin therapeutic regimen.

Severe Cutaneous and Mucocutaneous Reactions

Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis, some fatal, were reported in post-marketing experience. The time to onset of these reactions was variable, ranging from a few days to 4 months after administration of the Zevalin therapeutic regimen. Discontinue the Zevalin therapeutic regimen in patients experiencing a severe cutaneous or mucocutaneous reaction [see Boxed Warning and Adverse Reactions (6.3)].

Altered Biodistribution

In a post-marketing registry designed to collect biodistribution images and other information in reported cases of altered biodistribution, there were 12 (1.3%) patients reported to have altered biodistribution among 953 patients registered.

Leukemia and Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML) were reported in 5.2% (11/211) of patients with relapsed or refractory NHL enrolled in clinical studies and 1.5% (8/535) of patients included in the expanded-access trial, with median follow-up of 6.5 and 4.4 years, respectively. Among the 19 reported cases, the median time to the diagnosis of MDS or AML was 1.9 years following treatment with the Zevalin therapeutic regimen; however, the cumulative incidence continues to increase [see Adverse Reactions (6.1)].

Among 204 patients receiving Y-90 Zevalin following first-line chemotherapy, two patients (1%) were diagnosed with AML within 3 years of receiving Zevalin.

Embryo-Fetal Toxicity

Based on its radioactivity, Y-90 Zevalin may cause fetal harm when administered to a pregnant woman. If the Zevalin therapeutic regimen is administered during pregnancy, the patient should be apprised of the potential hazard to a fetus. Advise women of childbearing potential to use adequate contraception for a minimum of twelve months [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1), and Patient Counseling Information (17)]].

Extravasation

Monitor patients closely for evidence of extravasation during Zevalin infusion. Immediately terminate the infusion if signs or symptoms of extravasation occur and restart in another limb  [see Dosage and Administration (2.2)].

Immunization

The safety of immunization with live viral vaccines following the Zevalin therapeutic regimen has not been studied. Do not administer live viral vaccines to patients who have recently received Zevalin. The ability to generate an immune response to any vaccine following the Zevalin therapeutic regimen has not been studied.

Laboratory Monitoring

Monitor complete blood counts (CBC) and platelet counts following the Zevalin therapeutic regimen weekly until levels recover or as clinically indicated.

Radionuclide Precautions

During and after radiolabeling Zevalin with Y-90, minimize radiation exposure to patients and to medical personnel, consistent with institutional good radiation safety practices and patient management procedures.

Creutzfeldt-Jakob Disease (CJD)

The Zevalin therapeutic regimen contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, Zevalin carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

Adverse Reactions

The following serious adverse reactions are discussed in greater detail in other sections of the label:

• Serious Infusion Reactions [see Boxed Warning and  Warnings and Precautions (5.1)].


• Prolonged and Severe Cytopenias [see Boxed Warning and  Warnings and Precautions (5.2)].


• Severe Cutaneous and Mucocutaneous Reactions [see Boxed Warning and  Warnings and Precautions (5.3)].


• Leukemia and Myelodysplastic Syndrome [see Warnings and Precautions (5.5)].

The most common adverse reactions of Zevalin are cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea, and pyrexia.

The most serious adverse reactions of Zevalin are prolonged and severe cytopenias (thrombocytopenia, anemia, lymphopenia, neutropenia) and secondary malignancies.

Because the Zevalin therapeutic regimen includes the use of rituximab, see prescribing information for rituximab.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The reported safety data reflects exposure to Zevalin in 349 patients with relapsed or refractory, low-grade, follicular or transformed NHL across 5 trials (4 single arm and 1 randomized) and in 206 patients with previously untreated follicular NHL in a randomized trial (Study 4) who received any portion of the Zevalin therapeutic regimen. The safety data reflect exposure to Zevalin in 270 patients with relapsed or refractory NHL with platelet counts ≥150,000/ mm3 who received 0.4 mCi/kg (14.8 MBq/kg) of Y-90 Zevalin (Group 1 in Table 4), 65 patients with relapsed or refractory NHL with platelet counts of 100,000 to 149,000/mm3 who received 0.3 mCi/kg (11.1 MBq/kg) of Y-90 Zevalin (Group 2 in Table 4), and 204 patients with previously untreated NHL with platelet counts ≥150,000/ mm3 who received 0.4 mCi/kg (14.8 MBq/kg) of Y-90 Zevalin; all patients received a single course of Zevalin.

Table 2 displays selected adverse reaction incidence rates in patients who received any portion of the Zevalin therapeutic regimen (n=206) or no further therapy (n=203) following first-line chemotherapy (Study 4).

Table 2. Per-Patient Incidence (%) of Selected* Adverse Reactions Occurring in ≥ 5% of Patients with Previously Untreated Follicular NHL Treated with the Zevalin Therapeutic Regimen

* Between-group difference of ≥5% † NCI CTCAE version 2.0
	Zevalin (n=206)		Observation (n=203)
	All Grades†	Grade† 3-4	All Grades†	Grade† 3-4
	%	%	%	%
Gastrointestinal Disorders
Abdominal pain	17	2	13	<1
Diarrhea	11	0	3	0
Nausea	18	0	2	0
Body as a Whole
Asthenia	15	1	8	<1
Fatigue	33	1	9	0
Influenza-like illness	8	0	3	0
Pyrexia	10	3	4	0
Musculoskeletal
Myalgia	9	0	3	0
Metabolism
Anorexia	8	0	2	0
Respiratory, Thoracic & Media
Cough	11	<1	5	0
Pharyngolaryngeal pain	7	0	2	0
Epistaxis	5	2	<1	0
Nervous System
Dizziness	7	0	2	0
Vascular
Hypertension	7	3	2	<1
Skin & Subcutaneous
Night sweats	8	0	2	0
Petechiae	8	2	0	0
Pruritus	7	0	1	0
Rash	7	0	<1	0
Infections & Infestations
Bronchitis	8	0	3	0
Nasopharyngitis	19	0	10	0
Rhinitis	8	0	2	0
Sinusitis	7	<1	<1	0
Urinary tract infection	7	<1	3	0
Blood and Lymphatic System
Thrombocytopenia	62	51	1	0
Neutropenia	45	41	3	2
Anemia	22	5	4	0
Leukopenia	43	36	4	1
Lymphopenia	26	18	9	5

Table 3 shows hematologic toxicities in 349 Zevalin-treated patients with relapsed or refractory, low-grade, follicular or transformed B-cell NHL. Grade 2-4 hematologic toxicity occurred in 86% of Zevalin-treated patients.

Table 3. Per-Patient Incidence (%) of Hematologic Adverse Reactions in Patients with Relapsed or Refractory Low-grade, Follicular or Transformed B-cell NHL* (N = 349)

* Occurring within the 12 weeks following the first rituximab infusion of the Zevalin therapeutic regimen
	All Grades %	Grade 3-4 %
Thrombocytopenia	95	63
Neutropenia	77	60
Anemia	61	17
Ecchymosis	7	<1

Prolonged and Severe Cytopenias

Patients in clinical studies were not permitted to receive hematopoietic growth factors beginning 2 weeks prior to administration of the Zevalin therapeutic regimen.

The incidence and duration of severe hematologic toxicity in previously treated NHL patients (N=335) and in previously untreated patients (Study 4) receiving Y-90 Zevalin are shown in Table 4.

Table 4. Severe Hematologic Toxicity in Patients Receiving Zevalin

* Day from last ANC ≥1000/mm3 to first ANC ≥1000/mm3 following nadir, censored at next treatment or  death † Day from nadir to first count at level of Grade 1 toxicity or baseline ‡ Day from last platelet count ≥50,000/mm3 to day of first platelet count ≥50,000/mm3 following nadir, censored at next treatment or death
Baseline Platelet Count	Group 1 (n=270) ≥ 150,000/mm3	Group 2 (n=65 ) 100,000 to 149,000/mm3	Study 4 (n=204) ≥ 150,000/mm3
Y-90 Zevalin Dose	0.4 mCi/kg (14.8 MBq/kg)	0.3 mCi/kg (11.1 MBq/kg)	0.4 mCi/kg (14.8 MBq/kg)
ANC
Median nadir ( per mm3)	800	600	721
Per Patient Incidence ANC <1000/mm3	57%	74%	65%
Per Patient Incidence ANC <500/mm3	30%	35%	26%
Median Duration (Days)*  ANC <1000/mm3	22	29	29
Median Time to Recovery†	12	13	15
Platelets
Median nadir (per mm3)	41,000	24,000	42,000
Per Patient Incidence Platelets <50,000/mm3	61%	78%	61%
Per Patient Incidence Platelets <10,000/mm3	10%	14%	4%
Median Duration (Days)‡ Platelets <50,000/mm3	24	35	26
Median Time to Recovery†	13	14	14

Cytopenias were more severe and more prolonged among eleven (5%) patients who received Zevalin after first-line fludarabine or a fludarabine-containing chemotherapy regimen as compared to patients receiving non-fludarabine-containing regimens. Among these eleven patients, the median platelet nadir was 13,000/mm3 with a median duration of platelets below 50,000/mm3 of 56 days and the median time for platelet recovery from nadir to Grade 1 toxicity or baseline was 35 days. The median ANC was 355/mm3, with a median duration of ANC below 1,000/mm3 of 37 days and the median time for ANC recovery from nadir to Grade 1 toxicity or baseline was 20 days.

The median time to cytopenia was similar across patients with relapsed/refractory NHL and those completing first-line chemotherapy, with median ANC nadir at 61-62 days, platelet nadir at 49-53 days, and hemoglobin nadir at 68-69 days after Y-90-Zevalin administration.

Information on hematopoietic growth factor use and platelet transfusions is based on 211 patients with relapsed/refractory NHL and 206 patients following first-line chemotherapy. Filgrastim was given to 13% of patients and erythropoietin to 8% with relapsed or refractory disease; 14% of patients receiving Zevalin following first-line chemotherapy received granulocyte-colony stimulating factors and 5% received erythopoiesis-stimulating agents. Platelet transfusions were given to approximately 22% of all Zevalin-treated patients. Red blood cell transfusions were given to 20% of patients with relapsed or refractory NHL and 2% of patients receiving Zevalin following first-line chemotherapy.

Infections

In relapsed or refractory NHL patients, infections occurred in 29% of 349 patients during the first 3 months after initiating the Zevalin therapeutic regimen and 3% developed serious infections (urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infection). Life-threatening infectio

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Gamimune N

Generic Name: immune globulin (Intramuscular route, Intravenous route, Subcutaneous route)

i-MUNE GLOB-ue-lin

Intravenous route(Powder for Solution;Solution)

Immune globulin intravenous (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Use caution in patients predisposed to acute renal failure and administer at the minimum concentration available and the minimum rate of infusion practicable in such patients. Higher rates of renal failure were associated with IGIV products containing sucrose . Flebogamma(R) 5%, Flebogamma(R) 5% DIF, Flebogamma(R) 10% DIF, Gammagard (R), Gamunex(R)-C, and Previgen(R) do not contain sucrose . Glycine is used as a stabilizer in Gamunex(R)-C .

Subcutaneous route(Solution)

Immune globulin intravenous (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Use caution in patients predisposed to acute renal failure and administer at the minimum concentration available and the minimum rate of infusion practicable in such patients. Higher rates of renal failure were associated with IGIV products containing sucrose. Gammagard(R) does not contain sucrose .

Commonly used brand name(s)

In the U.S.

• Baygam


• Carimune


• Gamimune N


• Gammagard


• Gammar-P


• Hizentra


• Iveegam EN


• Octagam


• Panglobulin NF


• Polygam S/D


• Sandoglobulin


• Vivaglobin

Available Dosage Forms:

• Solution


• Powder for Solution

Therapeutic Class: Immune Serum

Uses For Gamimune N

Immune globulin injection belongs to a group of medicines known as immunizing agents. It is used to prevent or treat diseases that occur when your body has a weak immune system. Immune globulin contains antibodies that make your immune system stronger. It is used for patients who have primary humoral immunodeficiency (PI), idiopathic thrombocytopenic purpura (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP).

This medicine is to be administered only by or under the supervision of your doctor.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, immune globulin is used in certain patients with the following medical conditions:

• Chronic parvovirus B19 infection (treatment).


• Dermatomyositis (treatment).


• Guillain-Barré syndrome (treatment).


• Hyperimmunoglobulinemia E syndrome (treatment).


• Infections in low-birth-weight preterm high-risk neonates (prophylaxis and treatment adjunct).


• Lambert-Eaton myasthenic syndrome (treatment).


• Multifocal motor neuropathy (treatment).


• Relapsing-remitting multiple sclerosis (treatment).

Before Using Gamimune N

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of immune globulin injection in children. However, safety and efficacy have not been established in children with CIDP, safety and efficacy have not been established for Flebogamma® and subcutaneous injection of Gamunex®-C in children with PI, and safety and efficacy have not been established for Gammagard Liquid and Vivaglobin® in children younger than 2 years of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of immune globulin injection in the elderly. However, elderly patients are more likely to have age-related blood clotting problems, kidney disease, or heart disease, which may require caution for patients receiving immune globulin injection.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Anemia, history of or


• Bleeding problems, history of or


• Hyponatremia (low sodium in the blood) or


• Kidney problems—Use with caution. May make these conditions worse.

• Atherosclerosis (hardening of the arteries), history of or


• Blood clotting problems, history of or


• Diabetes or


• Heart attack or stroke, recent or


• Heart or blood vessel disease or


• Hyperproteinemia (high protein in the blood) or


• Hyperviscosity (thick blood), known or suspected or


• Hypovolemia (low blood volume or major loss of body fluids) or


• IgA (immunoglobulin A) deficiency with antibodies against IgA or


• Paraproteinemia (paraproteins in the blood) or


• Sepsis (serious infection in the body)—Use with caution. May cause side effects to become worse.

Proper Use of immune globulin

This section provides information on the proper use of a number of products that contain immune globulin. It may not be specific to Gamimune N. Please read with care.

A doctor or other trained health professional will give you or your child this medicine. This medicine is given through a needle placed in one of your veins, as a shot into one of your muscles, or as a shot under your skin.

This medicine comes with a patient information insert. Read and follow the instructions carefully. Ask your doctor if you have any questions.

While you or your child are being treated with immune globulin injection, do not have any immunizations (vaccines) without your doctor's approval. Live virus vaccines should not be given for 3 months after receiving immune globulin.

The Gammagard Liquid, Gamunex®-C, Hizentra®, and Vivaglobin® products may sometimes be given at home to patients who do not need to be in the hospital or clinic. They are given as an infusion under your skin once every week. If you or your child are using this medicine at home, your doctor will teach you how to prepare and infuse the medicine. Be sure you understand how to use the medicine.

Do not change the brand or type of your immune globulin unless your doctor tells you to. If you or your child must change the brand or type of medicine, talk to your doctor before giving yourself an injection.

If you or your child are using Gammagard Liquid, Gamunex®-C, Hizentra®, or Vivaglobin® at home, you will be shown the body areas where the medicine can be given. Use a different body area each time you give yourself an infusion. Keep track of where you give each infusion to make sure you rotate body areas. This will help prevent skin problems.

Allow the Gammagard Liquid, Gamunex®-C, or Vivaglobin® brand to reach room temperature before using it.

To use Gammagard Liquid, Gamunex®-C, Hizentra®, or Vivaglobin®:

• First, gather the items you will need on a clean, flat surface using a cloth or towel in a well-lighted area.


• Wash your hands with soap and water before and after using this medicine.


• If you have been told to wear gloves when preparing your infusion, put the gloves on.


• Check the liquid in the vial (glass container). It should be clear and slightly yellow to light brown in color. If it is cloudy, discolored, or contains large flecks (particles), do not use the vial. Select another vial.


• If the liquid is clear, place it on the clean, flat surface. Do not heat up or shake the medicine.


• Follow your doctor's instructions on how to prepare the correct amount of medicine.


• Choose an injection site on your body (e.g., abdomen or stomach area, thigh, upper arm, upper leg, or hip). Clean the injection site with a fresh alcohol wipe, and let it dry.


• With two fingers, pinch together the skin at the injection site. Insert the needle with the tube under the skin.


• Put sterile gauze and tape over the injection site to keep the needle from coming out.


• Before starting the infusion, make sure no blood is flowing into the infusion tube. If blood is present, remove and throw away the used needle and tube.


• Follow your doctor's instructions on how to use the infusion pump.


• Remove the peel-off portion of the label from the used vial. Place this label in your treatment diary or log book. Write down the amount of medicine you used, the date, and the time of your treatment.


• It usually takes about 60 minutes for each infusion.


• When all of the medicine has been infused, turn off the pump.


• Take the gauze off and remove the needle and tube from your skin.


• Clean and store the infusion pump.


• Throw away used needles and tubes in a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.

Missed Dose

This medicine needs to be given on a fixed schedule. If you miss a dose or forget to use your medicine, call your doctor or pharmacist for instructions.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the Hizentra® product at room temperature, away from heat and moisture. Keep from freezing.

Protect the Hizentra® product from direct light. Keep the medicine in the original package until you are ready to use it.

Store the Gamunex®-C and Vivaglobin® products in the refrigerator, but do not freeze the medicine. Store it in the original container.

You may store the Gammagard Liquid product in the refrigerator for 36 months, or at room temperature for up to 12 months (if within the first 24 months of the date of manufacture). Check the box for the date of manufacture. Store it in the original container. Do not freeze. Talk with your pharmacist if you have questions about storage of this product.

Precautions While Using Gamimune N

It is very important that your doctor check the progress of you or your child at regular visits for any problems that may be caused by this medicine. Blood and urine tests may be needed to check for unwanted effects.

Patients with idiopathic thrombocytopenic purpura (ITP) should not be treated with Gamunex®-C that is injected under the skin (subcutaneously). Doing so may increase the risk of having a hematoma (buildup of blood under the skin).

This medicine may cause fever, chills, flushing, headaches, nausea, and vomiting, especially if you are receiving it for the first time or if you have not received it for more than 8 weeks. Check with your doctor or nurse right away if you have any of these symptoms.

This medicine is made from donated human blood. Some human blood products have transmitted certain viruses to people who have received them. The risk of getting a virus from medicines made from human blood has been greatly reduced in recent years. This is the result of required testing of human donors for certain viruses, and required testing of the medicine when it is made. Although the risk is low, talk with your doctor if you have concerns.

This medicine may cause a serious type of allergic reaction, including anaphylaxis, which can be life-threatening and requires immediate medical attention. Tell your doctor right away if you or your child have a rash, itching, hives, chest pain, dizziness or lightheadedness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth after receiving this medicine. Certain people, including those with IgA (an immunoglobulin) deficiency and antibodies against IgA and a history of hypersensitivity to human immunoglobulin products should not use this medicine.

Check with your doctor right away if you or your child start to have a stiff neck, drowsiness, fever, severe headache, nausea or vomiting, painful eye movements, or eye sensitivity to light. These could be symptoms of a serious condition called aseptic meningitis syndrome (AMS).

This medicine may cause bleeding (hemolysis) or hemolytic anemia. Tell your doctor right away if you or your child have stomach or back pain, dark urine, decreased urination, difficulty with breathing, an increased heart rate, tiredness, or yellow eyes or skin after you receive the medicine.

Check with your doctor right away if you or your child start having chest pain; difficult, fast, or noisy breathing, sometimes with wheezing; blue lips and fingernails; fever; pale skin; increased sweating; coughing that sometimes produces a pink frothy sputum; shortness of breath; or swelling of the legs and ankles, after receiving this medicine. These may be symptoms of a serious lung problem.

This medicine may cause blood clots. This is more likely to occur if you have a history of blood clotting problems, heart disease, or atherosclerosis (hardening of the arteries), or if you are obese, take medicines containing estrogen, or must stay in bed for a long time because of surgery or illness. Check with your doctor right away if you or your child suddenly have chest pain, shortness of breath, a severe headache, leg pain, or problems with vision, speech, or walking. .

Check with your doctor right away if you or your child start having red or dark brown urine; lower back or side pain; a sudden weight gain; a swollen face, arms, or legs; decreased urine output; or any problems with urination after you receive this medicine. These may be symptoms of a serious kidney problem.

Make sure any doctor or dentist who treats you knows that you are using this medicine. This medicine may affect the results of certain medical tests.

Gamimune N Side Effects

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

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

More common

• Chills


• cough


• difficulty with breathing


• fast, pounding, or irregular heartbeat or pulse


• fever


• noisy breathing


• shortness of breath


• tightness in the chest


• troubled breathing


• unusual tiredness or weakness

Less common

• Bluish coloring of the lips or nailbeds


• burning sensation in the head


• faintness or lightheadedness

Rare

• Difficulty with swallowing


• hives or welts


• itching, especially of the feet or hands


• reddening of the skin, especially around the ears


• swelling of the eyes, face, or inside of the nose

Incidence not known

• Back, leg, or stomach pains


• bleeding gums


• blistering, peeling, or loosening of the skin


• bloody, black, or tarry stools


• blurred vision


• change in consciousness


• chest pain or discomfort


• cold, clammy, or pale skin


• confusion


• convulsions


• coughing that sometimes produces a pink frothy sputum


• dark urine


• decrease in urine amount


• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position


• fever with or without chills


• headache that is severe and occurs suddenly


• increased sweating


• light-colored stools


• loss of appetite


• loss of bladder control


• loss of consciousness


• low blood pressure or pulse


• muscle spasm or jerking of all extremities


• nausea or vomiting


• nosebleeds


• painful or difficult urination


• pains in the chest, groin, or legs, especially calves of the legs


• red skin lesions, often with a purple center


• red, irritated eyes


• shakiness in the legs, arms, hands, or feet


• shivering


• skin blisters


• slurred speech that occurs suddenly


• slow breathing


• sores, ulcers, or white spots in the mouth or on the lips


• sudden loss of consciousness


• sudden loss of coordination


• sudden vision changes


• sudden, severe weakness or numbness in the arm or leg


• sweating


• swelling in the legs and ankles


• tightness in the chest


• trembling or shaking of the hands or feet


• unusual bleeding or bruising


• yellow eyes or skin

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

More common

• Diarrhea


• dizziness


• headache


• joint pain


• muscle pain


• redness, swelling, itching, or pain at the injection site


• skin rash

Less common

• Hip pain


• leg cramps

Incidence not known

• Feeling of warmth


• redness of the face, neck, arms, and occasionally, upper chest


• stomach pain


• swollen glands


• tiredness


• weakness

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

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

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

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Fentanyl Transdermal

Fentanyl Transdermal System C-II

Revised: November 2011

Rx only

Full Prescribing Information

FOR USE IN OPIOID-TOLERANT PATIENTS ONLY

BOXED WARNING SECTION

Fentanyl Transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the patches (Fentanyl Transdermal system) may be a particular target for abuse and diversion.

Fentanyl Transdermal system is indicated for management of persistent, moderate to severe chronic pain that:

• 
  

  requires continuous, around-the-clock opioid administration for an extended period of time, and

  
  


• 
  

  cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids

  
  

Fentanyl Transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to Fentanyl Transdermal system 25 mcg/h. Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid.

Because serious or life-threatening hypoventilation could occur, Fentanyl Transdermal system is contraindicated:

• 
  

  in patients who are not opioid-tolerant

  
  


• 
  

  in the management of acute pain or in patients who require opioid analgesia for a short period of time

  
  


• 
  

  in the management of post-operative pain, including use after out-patient or day surgeries (e.g., tonsillectomies)

  
  


• 
  

  in the management of mild pain

  
  


• 
  

  in the management of intermittent pain [e.g., use on an as needed basis (prn)]

  
  

(See CONTRAINDICATIONS for further information.)

Since the peak fentanyl levels occur between 24 and 72 hours of treatment, prescribers should be aware that serious or life threatening hypoventilation may occur, even in opioid-tolerant patients, during the initial application period.

The concomitant use of Fentanyl Transdermal system with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.  Patients receiving Fentanyl Transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted. (See CLINICAL PHARMACOLOGY – Drug Interactions, WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION for further information).

The safety of Fentanyl Transdermal system has not been established in children under 2 years of age. Fentanyl Transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS – Pediatric Use).

Fentanyl Transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the Fentanyl Transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean elimination half-life of 17 hours of Fentanyl Transdermal system, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours.

Fentanyl Transdermal system can be abused in a manner similar to other opioid agonists, legal or illicit. This risk should be considered when administering, prescribing, or dispensing Fentanyl Transdermal system in situations where the healthcare professional is concerned about increased risk of misuse, abuse or diversion.

Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse, abuse and addiction. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction.

Fentanyl Transdermal systems are intended for transdermal use (on intact skin) only. Do not use a Fentanyl Transdermal system patch if the seal is broken or the patch is cut, damaged, or changed in any way. Using a patch that is cut, damaged, or changed in any way can expose the patient or caregiver to the contents of the patch, which can result in an overdose of fentanyl that may be fatal.

Avoid exposing the Fentanyl Transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, while wearing the system. Avoid taking hot baths or sunbathing. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. Patients wearing Fentanyl Transdermal systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the Fentanyl Transdermal system dose should be adjusted if necessary.

Fentanyl Transdermal Description

Fentanyl Transdermal system is a transdermal system providing continuous systemic delivery of fentanyl, a potent opioid analgesic, for 72 hours. The chemical name is N-Phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide. The structural formula is:

The molecular weight of fentanyl base is 336.5, and the molecular formula is C22H28N2O. The n-octanol:water partition coefficient is 860:1. The pKa is 8.4.

System Components and Structure

The amount of fentanyl released from each system per hour is proportional to the surface area (25 mcg/h per 10 cm2). The composition per unit area of all system sizes is identical. Each system also contains 0.1 mL of alcohol USP per 10 cm2.

Dose* (mcg/h)	Size (cm2)	Fentanyl Content (mg)
*Nominal delivery rate per hour
25	10	2.5
50	20	5
75	30	7.5
100	40	10

Fentanyl Transdermal system is a rectangular transparent unit comprising a protective liner and four functional layers. Proceeding from the outer surface toward the surface adhering to skin, these layers are:

1) a backing layer of polyester film; 2) a drug reservoir of fentanyl and alcohol USP gelled with hydroxyethyl cellulose; 3) an ethylene-vinyl acetate copolymer membrane that controls the rate of fentanyl delivery to the skin surface; and 4) a fentanyl containing silicone adhesive. Before use, a protective liner covering the adhesive layer is removed and discarded.

The active component of the system is fentanyl. The remaining components are pharmacologically inactive. Less than 0.2 mL of alcohol is also released from the system during use.

Fentanyl Transdermal - Clinical Pharmacology

Pharmacology

Fentanyl is an opioid analgesic. Fentanyl interacts predominantly with the opioid mu-receptor. These mu-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.

In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Analgesic blood levels of fentanyl may cause nausea and vomiting directly by 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 fentanyl. 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 clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration. Clinical assays show no clinically significant histamine release in dosages up to 50 mcg/kg.

Pharmacokinetics (see graph and tables)

Fentanyl Transdermal system releases fentanyl from the reservoir at a nearly constant amount per unit time. The concentration gradient existing between the saturated solution of drug in the reservoir and the lower concentration in the skin drives drug release. Fentanyl moves in the direction of the lower concentration at a rate determined by the copolymer release membrane and the diffusion of fentanyl through the skin layers. While the actual rate of fentanyl delivery to the skin varies over the 72-hour application period, each system is labeled with a nominal flux which represents the average amount of drug delivered to the systemic circulation per hour across average skin.

While there is variation in dose delivered among patients, the nominal flux of the systems (25, 50, 75, and 100 mcg of fentanyl per hour) is sufficiently accurate as to allow individual titration of dosage for a given patient. The small amount of alcohol which has been incorporated into the system enhances the rate of drug flux through the rate-limiting copolymer membrane and increases the permeability of the skin to fentanyl.

Following Fentanyl Transdermal system application, the skin under the system absorbs fentanyl, and a depot of fentanyl concentrates in the upper skin layers. Fentanyl then becomes available to the systemic circulation. Serum fentanyl concentrations increase gradually following initial Fentanyl Transdermal system application, generally leveling off between 12 and 24 hours and remaining relatively constant, with some fluctuation, for the remainder of the 72-hour application period.  Peak serum concentrations of fentanyl generally occurred between 24 and 72 hours after initial application (see Table A). Serum fentanyl concentrations achieved are proportional to the Fentanyl Transdermal system delivery rate. With continuous use, serum fentanyl concentrations continue to rise for the first few system applications. After several sequential 72-hour applications, patients reach and maintain a steady state serum concentration that is determined by individual variation in skin permeability and body clearance of fentanyl (see graph and Table B).

The kinetics of fentanyl in normal subjects following application of a 100 mcg/hr Fentanyl Transdermal system patch were bioequivalent with or without a Bioclusive™ overlay (polyurethane film dressing).

After system removal, serum fentanyl concentrations decline gradually, falling about 50% in approximately 17 (range 13 to 22) hours. Continued absorption of fentanyl from the skin accounts for a slower disappearance of the drug from the serum than is seen after an IV infusion, where the apparent half-life is approximately 7 (range 3 to 12) hours.

TABLE A FENTANYL PHARMACOKINETIC PARAMETERS FOLLOWING FIRST 72-HOUR APPLICATION OF A Fentanyl Transdermal SYSTEM

	Mean (SD) Time to  Maximal Concentration Tmax (h)	Mean (SD) Maximal Concentration Cmax (ng/mL)
Fentanyl Transdermal System 25 mcg/h	38.1 (18.0)	0.6 (0.3)
Fentanyl Transdermal System 50 mcg/h	34.8 (15.4)	1.4 (0.5)
Fentanyl Transdermal System 75 mcg/h	33.5 (14.5)	1.7 (0.7)
Fentanyl Transdermal System 100 mcg/h	36.8 (15.7)	2.5 (1.2)

NOTE: After system removal there is continued systemic absorption from residual fentanyl in the skin so that serum concentrations fall 50%, on average, in 17 hours.

TABLE B RANGE OF PHARMACOKINETIC PARAMETERS OF INTRAVENOUS FENTANYL IN PATIENTS

	Clearance (L/h) Range [70 kg]	Volume of Distribution VSS (L/kg) Range	Half-Life T1/2 (h) Range
+Estimated
Surgical Patients	27 – 75	3 – 8	3 – 12
Hepatically Impaired Patients	3 – 80+	0.8 – 8+	4 – 12+
Renally Impaired Patients	30 – 78	--	--

NOTE: Information on volume of distribution and half-life not available for renally impaired patients.

Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. Fentanyl accumulates in the skeletal muscle and fat and is released slowly into the blood. The average volume of distribution for fentanyl is 6 L/kg (range 3 to 8, N=8).

Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system. In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. 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. Mean values for unbound fractions of fentanyl in plasma are estimated to be between 13 and 21%.

Skin does not appear to metabolize fentanyl delivered transdermally. This was determined in a human keratinocyte cell assay and in clinical studies in which 92% of the dose delivered from the system was accounted for as unchanged fentanyl that appeared in the systemic circulation.

Special Populations

Hepatic or Renal Disease

Insufficient information exists to make recommendations regarding the use of Fentanyl Transdermal system in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

Pediatric Use

In 1.5 to 5 year old, non-opioid-tolerant pediatric patients, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults. However, these findings have been taken into consideration in determining the dosing recommendations for opioid-tolerant pediatric patients (2 years of age and older). For pediatric dosing information, refer to DOSAGE AND ADMINISTRATION section.


Geriatric Use

Information from a pilot study of the pharmacokinetics of IV fentanyl in geriatric patients (N=4) indicates that the clearance of fentanyl may be greatly decreased in the population above the age of 60. The relevance of these findings to Fentanyl Transdermal system is unknown at this time.

Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients or when opioids are given in conjunction with other agents that depress respiration.

Fentanyl Transdermal systems should be used with caution in elderly, cachectic or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting, or altered clearance (see DOSAGE AND ADMINISTRATION).

Drug Interactions

The interaction between ritonavir, a CPY3A4 inhibitor, and fentanyl was investigated in eleven healthy volunteers in a randomized crossover study. Subjects received oral ritonavir or placebo for 3 days. The ritonavir dose was 200 mg tid on Day 1 and 300 mg tid on Day 2 followed by one morning dose of 300 mg on Day 3. On Day 2, fentanyl was given as a single IV dose at 5 mcg/kg two hours after the afternoon dose of oral ritonavir or placebo. Naloxone was administered to counteract the side effects of fentanyl. The results suggested that ritonavir might decrease the clearance of fentanyl by 67%, resulting in a 174% (range 52% to 420%) increase in fentanyl AUC0-∞. Coadministration of ritonavir in patients receiving Fentanyl Transdermal system has not been studied; however, an increase in fentanyl AUC is expected. (see BOX WARNING, WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore, potential interactions may occur when Fentanyl Transdermal system is given concurrently with agents that affect CYP3A4 activity. Coadministration with agents that induce CYP3A4 activity may reduce the efficacy of Fentanyl Transdermal systems. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarmone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving Fentanyl Transdermal systems and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see BOX WARNING, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION for further information).

Pharmacodynamics

Ventilatory Effects

Because of the risk for serious or life-threatening hypoventilation, Fentanyl Transdermal system is CONTRAINDICATED in the treatment of post-operative and acute pain and in patients who are not opioid-tolerant. In clinical trials of 357 patients with acute pain treated with Fentanyl Transdermal system, 13 patients experienced hypoventilation. Hypoventilation was manifested by respiratory rates of less than 8 breaths/minute or a pCO2 greater than 55 mm Hg. In these studies, the incidence of hypoventilation was higher in nontolerant women (10) than in men (3) and in patients weighing less than 63 kg (9 of 13). Although patients with impaired respiration were not common in the trials, they had higher rates of hypoventilation. In addition, post-marketing reports have been received that describe opioid-naïve post-operative patients who have experienced clinically significant hypoventilation and death with Fentanyl Transdermal system.

While most adult and pediatric patients using Fentanyl Transdermal system chronically develop tolerance to fentanyl induced hypoventilation, episodes of slowed respirations may occur at any time during therapy.

Hypoventilation can occur throughout the therapeutic range of fentanyl serum concentrations, especially for patients who have an underlying pulmonary condition or who receive usual doses of opioids or other CNS drugs associated with hypoventilation in addition to Fentanyl Transdermal system. The use of Fentanyl Transdermal system is contraindicated in patients who are not tolerant to opioid therapy.

The use of Fentanyl Transdermal system should be monitored by clinical evaluation, especially within the initial 24 to 72 hours when serum concentrations from the initial patch will peak, and following increases in dosage. Fentanyl Transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older.

See BOX WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and OVERDOSAGE for additional information on hypoventilation.

Cardiovascular Effects

Fentanyl may infrequently produce bradycardia. The incidence of bradycardia in clinical trials with Fentanyl Transdermal system was less than 1%.

CNS Effects

Central nervous system effects increase with increasing serum fentanyl concentrations.

Indications and Usage for Fentanyl Transdermal

Fentanyl Transdermal system is indicated for management of persistent, moderate to severe chronic pain that:

• 
  

  requires continuous, around-the-clock opioid administration for an extended period of time, and

  
  


• 
  

  cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids.

  
  

Fentanyl Transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to Fentanyl Transdermal system 25 mcg/h (see DOSAGE AND ADMINISTRATION). Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid.

Because serious or life-threatening hypoventilation could result, Fentanyl Transdermal system is contraindicated for use on an as needed basis (i.e., prn), for the management of post-operative or acute pain, or in patients who are not opioid-tolerant or who require opioid analgesia for a short period of time. (see BOX WARNING and CONTRAINDICATIONS).

An evaluation of the appropriateness and adequacy of treating with immediate-release opioids is advisable prior to initiating therapy with any modified-release opioid. Prescribers should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen, to opioids, in a plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction.

Contraindications

Because serious or life-threatening hypoventilation could occur, Fentanyl Transdermal system is contraindicated:

• 
  

  in patients who are not opioid-tolerant

  
  


• 
  

  in the management of acute pain or in patients who require opioid analgesia for a short period of time

  
  


• 
  

  in the management of post-operative pain, including use after out-patient or day surgeries, (e.g., tonsillectomies)

  
  


• 
  

  in the management of mild pain

  
  


• 
  

  in the management of intermittent pain (e.g., use on an as needed basis [prn])

  
  


• 
  

  in situations of significant respiratory depression, especially in unmonitored settings where there is a lack of resuscitative equipment

  
  


• 
  

  in patients who have acute or severe bronchial asthma

  
  

Fentanyl Transdermal system is contraindicated in patients who have or are suspected of having paralytic ileus.

Fentanyl Transdermal system is contraindicated in patients with known hypersensitivity to fentanyl or any components of this product.

Warnings

Fentanyl Transdermal systems are intended for transdermal use (on intact skin) only. Do not use a Fentanyl Transdermal system patch if the seal is broken or the patch is cut, damaged, or changed in any way. Using a patch that is cut, damaged, or changed in any way can expose the patient or caregiver to the contents of the patch, which can result in an overdose of fentanyl that may be fatal.

The safety of Fentanyl Transdermal system has not been established in children under 2 years of age. Fentanyl Transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS – Pediatric Use).

Fentanyl Transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the Fentanyl Transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. The mean elimination half-life of Fentanyl Transdermal system is 17 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require monitoring for at least 24 hours after Fentanyl Transdermal system removal since serum fentanyl concentrations decline gradually and reach an approximate 50% reduction in serum concentrations 17 hours after system removal.

Fentanyl Transdermal system should be prescribed only by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of hypoventilation including the use of opioid antagonists.

All patients and their caregivers should be advised to avoid exposing the Fentanyl Transdermal system application site to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. Patients should be advised against taking hot baths or sunbathing. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death.

Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Patients wearing Fentanyl Transdermal systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the Fentanyl Transdermal system dose should be adjusted if necessary.

Death and other serious medical problems have occurred when people were accidentally exposed to Fentanyl Transdermal system. Examples of accidental exposure include transfer of a Fentanyl Transdermal system from an adult’s body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregiver’s skin to the medication in the patch while the caregiver was applying or removing the patch.

Placing Fentanyl Transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death.

Misuse, Abuse and Diversion of Opioids

Fentanyl is an opioid agonist of the morphine-type. Such drugs 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 opioids, legal or illicit. This should be considered when prescribing or dispensing Fentanyl Transdermal system in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion.

Fentanyl Transdermal system has been reported as being abused by other methods and routes of administration. These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and DRUG ABUSE AND ADDICTION).

Concerns about abuse, addiction and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

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.

Hypoventilation (Respiratory Depression)

Serious or life-threatening hypoventilation may occur at any time during the use of Fentanyl Transdermal system especially during the initial 24 to 72 hours following initiation of therapy and following increases in dose.

Because significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed, hypoventilation may persist beyond the removal of Fentanyl Transdermal system. 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.

Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in Fentanyl Transdermal system. Respiratory depression is more likely to occur in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.

Fentanyl Transdermal system should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of Fentanyl Transdermal system may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.

Chronic Pulmonary Disease

Because potent opioids can cause serious or life-threatening hypoventilation, Fentanyl Transdermal system should be administered with caution to patients with pre-existing medical conditions predisposing them to hypoventilation. In such patients, normal analgesic doses of opioids may further decrease respiratory drive to the point of respiratory failure.

Head Injuries and Increased Intracranial Pressure

Fentanyl Transdermal system 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. Fentanyl Transdermal system should be used with caution in patients with brain tumors.

Interactions with other CNS Depressants

The concomitant use of Fentanyl Transdermal system with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation or potentially result in coma. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced.

Interactions with Alcohol and Drugs of Abuse

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

Interactions with CYP3A4 Inhibitors

The concomitant use of Fentanyl Transdermal system with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving Fentanyl Transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted. (see BOX WARNING, CLINICAL PHARMACOLOGY – Drug Interactions, PRECAUTIONS and DOSAGE AND ADMINISTRATION for further information).

Precautions

General

Fentanyl Transdermal system should not be used to initiate opioid therapy in patients who are not opioid-tolerant. Children converting to Fentanyl Transdermal system should be opioid-tolerant and 2 years of age or older (see BOX WARNING.)

Patients, family members and caregivers should be instructed to keep patches (new and used) out of the reach of children and others for whom Fentanyl Transdermal system was not prescribed. A considerable amount of active fentanyl remains in Fentanyl Transdermal system even after use as directed. Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression that could result in death.

Cardiac Disease

Fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients with bradyarrhythmias.

Hepatic or Renal Disease

Insufficient information exists to make recommendations regarding the use of Fentanyl Transdermal system in patients with impaired renal or hepatic function. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

Use in Pancreatic/Biliary Tract Disease

Fentanyl Transdermal system may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like Fentanyl Transdermal system may cause increases in the serum amylase concentration.

Tolerance

Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical Dependence

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION - Discontinuation of Fentanyl Transdermal System).

Ambulatory Patients

Strong opioid analgesics impair the mental or physical abilities required for the performance of potentially dangerous tasks, such as driving a car or operating machinery. Patients who have been given Fentanyl Transdermal system should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug.

Information for Patients

Patients and their caregivers should be provided with a Medication Guide each time Fentanyl Transdermal system is dispensed because new information may be available.

Patients receiving Fentanyl Transdermal systems should be given the following instructions by the physician:

1. 
   

   Patients should be advised that Fentanyl Transdermal systems contain fentanyl, an opioid pain medicine similar to morphine, hydromorphone, methadone, oxycodone, and oxymorphone.

   
   


2. 
   

   Patients should be advised that each Fentanyl Transdermal system may be worn continuously for 72 hours, and that each patch should be applied to a different skin site after removal of the previous transdermal patch.

   
   


3. 
   

   Patients should be advised that Fentanyl Transdermal systems should be applied to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm. Additionally, patients should be advised of the following:

   
   
   • 
     

     In young children or persons with cognitive impairment, the patch should be put on the upper back to lower the chances that the patch will be removed and placed in the mouth.

     
     
   
   
   • 
     

     Hair at the application site should be clipped (not shaved) prior to patch application.

     
     
   
   
   • 
     

     If the site of Fentanyl Transdermal system application must be cleansed prior to application of the patch, do so with clear water.

     
     
   
   
   • 
     

     Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics.

     
     
   
   
   • 
     

     Allow the skin to dry completely prior to patch application.

     
     
   
   


4. 
   

   Patients should be advised that Fentanyl Transdermal system should be applied immediately upon removal from the sealed package and after removal of the protective liner. Additionally the patient should be advised of the following:

   
   
   • 
     

     The Fentanyl Transdermal system should not be used if the seal is broken, or if the patch is cut, damaged, or changed in any way. Using a patch that is cut, damaged, or changed in any way can expose the patient or caregiver to the contents of the patch, which can result in an overdose of fentanyl that may be fatal.

     
     
   
   
   • 
     

     The transdermal patch should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges.

     
     
   
   
   • 
     

     The patch should not be folded so that only part of the patch is exposed.

     
     
   
   


5. 
   

   Patients should be advised that the dose of Fentanyl Transdermal system or the number of patches applied to the skin should NEVER be adjusted without the prescribing healthcare professional’s instruction.

   
   


6. 
   

   Patients should be advised that while wearing the patch, they should avoid exposing the Fentanyl Transdermal system application site to direct external heat sources, such as:

   
   
   • 
     

     heating pads,

     
     
   
   
   • 
     

     electric blankets,

     
     
   
   
   • 
     

     sunbathing,

     
     
   
   
   • 
     

     heat or tanning lamps,

     
     
   
   
   • 
     

     saunas,

     
     
   
   
   • 
     

     hot tubs, or hot baths, and

     
     
   
   
   • 
     

     heated water beds, etc.

     
     
   
   


7. 
   

   Patients should also be advised of a potential for temperature dependent increases in fentanyl release from the patch that could result in an overdose of fentanyl; therefore, patients who develop a high fever or increased body temperature due to strenuous exertion while wearing the patch should contact their physician.

   
   


8. Patients should be advised that if they experience problems with adhesion of the Fentanyl Transdermal system, they may tape the edges of the patch with first aid tape. If problems with adhesion persist, patients may overlay the patch with a transparent adhesive film dressing (e.g., Bioclusive™ or Tegaderm™).


9. 
   

   Patients should be advised that if the patch falls off before 72 hours a new patch may be applied to a different skin site.

   
   


10. 
    

    Patients should be advised to fold (so that the adhesive side adheres to itself) and immediately flush down the toilet used Fentanyl Transdermal patches after removal from the skin.

    
    


11. 
    

    Patients should be instructed that, if the gel from the drug reservoir accidentally contacts the skin, the area should be washed clean with clear water and not soap, alcohol, or other chemicals, because these products may increase the ability of fentanyl to go through the skin.

    
    


12. 
    

    Patients should be advised that Fentanyl Transdermal system may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery).

    
    


13. 
    

    Patients should be advised to refrain from any potentially dangerous activity when starting on Fentanyl Transdermal system or when their dose is being adjusted, until it is established that they have not been adversely affected.

    
    


14. 
    

    Patients should be advised that Fentanyl Transdermal system should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers) because dangerous additive effects may occur, resulting in serious injury or death.

    
    


15. 
    

    Patients should be advised to consult their physician or pharmacist if other medications are being or will be used with Fentanyl Transdermal system.

    
    


16. 
    

    Patients should be advised of the potential for severe constipation.

    
    


17. 
    

    Patients should be advised that if they have been receiving treatment with Fentanyl Transdermal system and cessation of therapy is indicated, it may be appropriate to taper the Fentanyl Transdermal system dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms.

    
    


18. 
    

    Patients should be advised that Fentanyl Transdermal system contains fentanyl, a drug with a high potential for abuse.

    
    


19. 
    

    Patients, family members and caregivers should be advised to protect Fentanyl Transdermal system from theft or misuse in the work or home environment.

    
    


20. 
    

    Patients should be instructed to keep Fentanyl Transdermal system in a secure place out of the reach of children due to the high risk of fatal respiratory depression.

    
    


21. 
    

    Patients should be advised that Fentanyl Transdermal system should never be given to anyone other than the individual for whom it was prescribed because of the risk of death or other serious medical problems to that person for whom it was not intended.

    
    


22. 
    

    Patients should be informed that, if the patch dislodges and accidentally sticks to the skin of another person, they should immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual.

    
    


23. 
    

    When Fentanyl Transdermal system is no longer needed, the unused patches should be removed from their pouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet.

    
    


24. 
    

    Women of childbearing potential who become, or are planning to become pregnant, should be advised to consult a physician prior to initiating or continuing therapy with Fentanyl Transdermal system.

    
    


25. 
    

    Patients should be informed that accidental exposure or mis