Zenapax

daclizumab

Dosage Form: injection, solution, concentrate
Zenapax®

(daclizumab)

STERILE CONCENTRATE FOR INJECTION

Warning

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Zenapax® (daclizumab). The physician responsible for Zenapax administration should have complete information requisite for the follow-up of the patient. Zenapax should only be administered by healthcare personnel trained in the administration of the drug who have available adequate laboratory and supportive medical resources.

Zenapax Description

Zenapax® (daclizumab) is an immunosuppressive, humanized IgG1 monoclonal antibody produced by recombinant DNA technology that binds specifically to the alpha subunit (p55 alpha, CD25, or Tac subunit) of the human high-affinity interleukin-2 (IL-2) receptor that is expressed on the surface of activated lymphocytes.

Daclizumab is a composite of human (90%) and murine (10%) antibody sequences. The human sequences were derived from the constant domains of human IgG1 and the variable framework regions of the Eu myeloma antibody. The murine sequences were derived from the complementarity-determining regions of a murine anti-Tac antibody. The molecular weight predicted from the DNA sequence is 144 kilodaltons.

Zenapax 25 mg/5 mL is supplied as a clear, sterile, colorless concentrate for further dilution and intravenous administration. Each milliliter of Zenapax contains 5 mg of daclizumab and 3.6 mg sodium phosphate monobasic monohydrate, 11 mg sodium phosphate dibasic heptahydrate, 4.6 mg sodium chloride, 0.2 mg polysorbate 80, and may contain hydrochloric acid or sodium hydroxide to adjust the pH to 6.9. No preservatives are added.

Zenapax - Clinical Pharmacology

General

Mechanism of Action

Daclizumab functions as an IL-2 receptor antagonist that binds with high-affinity to the Tac subunit of the high-affinity IL-2 receptor complex and inhibits IL-2 binding. Daclizumab binding is highly specific for Tac, which is expressed on activated but not resting lymphocytes. Administration of Zenapax inhibits IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection.

While in the circulation, Zenapax impairs the response of the immune system to antigenic challenges. Whether the ability to respond to repeated or ongoing challenges with those antigens returns to normal after Zenapax is cleared is unknown (see PRECAUTIONS).

Pharmacokinetics

Adults

In clinical trials involving renal allograft patients treated with a 1 mg/kg IV dose of Zenapax every 14 days for a total of five doses, peak serum concentration (mean ± SD) rose between the first dose (21 ± 14 µg/mL) and fifth dose (32 ± 22 µg/mL). The mean trough serum concentration before the fifth dose was 7.6 ± 4.0 µg/mL. Population pharmacokinetic analysis of the data using a two-compartment open model gave the following values for a reference patient (45-year-old male Caucasian patient with a body weight of 80 kg and no proteinuria): systemic clearance = 15 mL/hour, volume of central compartment = 2.5 liter, volume of peripheral compartment = 3.4 liter. The estimated terminal elimination half-life for the reference patient was 20 days (480 hours), which is similar to the terminal elimination half-life for human IgG (18 to 23 days). Bayesian estimates of terminal elimination half-life ranged from 11 to 38 days for the 123 patients included in the population analysis. The influence of body weight on systemic clearance supports the dosing of Zenapax on a milligram per kilogram (mg/kg) basis. For patients studied, this dosing maintained drug exposure within 30% of the reference exposure. Covariate analyses showed that no dosage adjustments based on age, race, gender or degree of proteinuria, are required for renal allograft patients. The estimated interpatient variability (percent coefficient of variation) in systemic clearance and central volume of distribution were 15% and 27%, respectively.

Pediatrics

Pharmacokinetic parameters were evaluated in 61 pediatric patients treated with a 1 mg/kg IV dose of Zenapax every 14 days for a total of five doses. Peak serum concentration (mean ± SD) rose between the first dose (16 ± 12 µg/mL) and fifth dose (21 ± 14 µg/mL). The mean trough serum concentration before the fifth dose was 5.0 ± 2.7 µg/mL. Population pharmacokinetic analysis of the data using a two-compartment open model gave the following values for a reference patient (Caucasian patient with a body weight of 29.7 kg): systemic clearance = 10 mL/hour, volume of central compartment = 2.0 liter, volume of peripheral compartment = 1.4 liter. The estimated terminal elimination half-life for the reference patient was 13 days (317 hours). For the patients studied, this dosing maintained drug exposure within 50% of the reference exposure. Covariate analyses suggested that disposition parameters were not influenced to a clinically relevant extent by race, gender or degree of proteinuria. The estimated interpatient variability (percent coefficient of variation) in systemic clearance and central volume of distribution were 30% and 40%, respectively.

Pharmacodynamics

In vitro and in vivo data suggest that serum levels of 5 to 10 µg/mL are necessary for saturation of the Tac subunit of the IL-2 receptors to block the responses of activated T lymphocytes. At the recommended dosage regimen, daclizumab saturates the Tac subunit of the IL-2 receptor for approximately 90 and 120 days posttransplant, respectively in pediatric and adult patients. The duration of clinically significant IL-2 receptor blockade after the recommended course of Zenapax is not known. No significant changes to circulating lymphocyte numbers or cell phenotypes were observed by flow cytometry. Cytokine release syndrome has not been observed after Zenapax administration.

Clinical Studies

The safety and efficacy of Zenapax for the prophylaxis of acute organ rejection in adult patients receiving their first cadaveric kidney transplant were assessed in two randomized, double-blind, placebo-controlled, multicenter trials. These trials compared a dose of 1.0 mg/kg of Zenapax with placebo when each was administered as part of standard immunosuppressive regimens containing either cyclosporine and corticosteroids (double-therapy trial, no US sites) or cyclosporine, corticosteroids, and azathioprine (triple-therapy trial, predominantly US sites) to prevent acute renal allograft rejection. Zenapax dosing was initiated within 24 hours pretransplant, with subsequent doses given every 14 days for a total of five doses.

The primary efficacy endpoint of both trials was the proportion of patients who developed a biopsy-proven acute rejection episode within the first 6 months following transplantation. As shown in Table 1, this incidence was significantly lower in the group treated with Zenapax in both the double-therapy and triple-therapy trials.

Table 1 Efficacy Parameters

	Triple-therapy Regimen (cyclosporine, corticosteroids, and azathioprine)				Double-therapy Regimen (cyclosporine and corticosteroids)
	Placebo	Zenapax			Placebo	Zenapax
	(N=134)	(N=126)	p-value		(N=134)	(N=141)	p-value
n.s. = not significant
Incidence of biopsy-proven acute rejection at 6 months
No. of patients	47 (35%)	28 (22%)	0.03		63 (47%)	39 (28%)	0.001
Incidence of biopsy-proven acute rejection at 1 year
No. of patients	51 (38%)	35 (28%)	n.s.		65 (49%)	39 (28%)	<0.001
Graft survival at 3 years posttransplant
No. of patients with functioning graft	111 (83%)	106 (84%)	n.s.		105 (78%)	116 (82%)	n.s.
Patient survival at 3 years posttransplant
No. of patients	126 (94%)	116 (92%)	n.s.		118 (88%)	135 (96%)	0.02

Treatment with Zenapax was associated with better patient survival up to 3 years posttransplant in the double-therapy study. No difference in patient survival was observed in the triple-therapy study between patients treated with Zenapax or placebo up to 3 years posttransplant. No difference was observed for graft survival between treatment groups in both studies at 3 years posttransplant.

The incidence of delayed graft function was not different between patients treated with placebo or Zenapax in either study. No difference in graft function was observed 1 year and 3 years posttransplant in either study between patients treated with placebo or Zenapax.

In a randomized, double-blind study to assess tolerability, pharmacokinetics, and drug interactions in renal allograft recipients, Zenapax (50 patients) or placebo (25 patients) was added to an immunosuppressive regimen of cyclosporine, mycophenolate mofetil, and corticosteroids. In this study, the addition of Zenapax did not result in an increased incidence of adverse events or a change in the types of adverse events reported. The incidence of the combined endpoint of biopsy-proven or clinically presumptive acute rejection was 20% (5 of 25 patients) in the placebo group and 12% (6 of 50 patients) in the Zenapax group. Although numerically lower, the difference in acute rejection was not significant. However, in a randomized, double-blind, placebo-controlled trial of Zenapax in cardiac transplant recipients (n=434) receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality was increased in patients randomized to receive Zenapax compared with those randomized to receive placebo (see WARNINGS and ADVERSE REACTIONS).

INDICATION AND USAGE

Zenapax is indicated for the prophylaxis of acute organ rejection in patients receiving renal transplants. It is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids.

The efficacy of Zenapax for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been demonstrated.

CONTRAINDICATION

Zenapax is contraindicated in patients with known hypersensitivity to daclizumab or to any components of this product.

WARNINGS (see Boxed WARNING)

The use of Zenapax as part of an immunosuppressive regimen including cyclosporine, mycophenolate mofetil, and corticosteroids may be associated with an increase in mortality. In a randomized, double-blind, placebo-controlled trial of Zenapax for the prevention of allograft rejection in 434 cardiac transplant recipients receiving concomitant cyclosporine, mycophenolate mofetil, and corticosteroids, mortality at 6 and 12 months was increased in those patients receiving Zenapax compared to those receiving placebo (7% vs 5%, respectively at 6 months; 10% vs 6% respectively at 12 months). Some, but not all, of the increase in mortality appeared related to a higher incidence of severe infections. Concomitant use of anti-lymphocyte antibody therapy may also be a factor in some of the fatal infections.

Zenapax should be administered under qualified medical supervision. Patients should be informed of the potential benefits of therapy and the risks associated with administration of immunosuppressive therapy.

While the incidence of lymphoproliferative disorders and opportunistic infections in the limited clinical trial experience was no higher in patients treated with Zenapax compared with placebo-treated patients, patients on immunosuppressive therapy are at increased risk for developing lymphoproliferative disorders and opportunistic infections and should be monitored accordingly.

Hypersensitivity

Severe, acute (onset within 24 hours) hypersensitivity reactions including anaphylaxis have been observed both on initial exposure to Zenapax and following re-exposure. These reactions may include hypotension, bronchospasm, wheezing, laryngeal edema, pulmonary edema, cyanosis, hypoxia, respiratory arrest, cardiac arrhythmia, cardiac arrest, peripheral edema, loss of consciousness, fever, rash, urticaria, diaphoresis, pruritus, and/or injection site reactions. If a severe hypersensitivity reaction occurs, therapy with Zenapax should be permanently discontinued. Medications for the treatment of severe hypersensitivity reactions including anaphylaxis should be available for immediate use. Patients previously administered Zenapax should only be re-exposed to a subsequent course of therapy with caution. The potential risks of such re-administration, specifically those associated with immunosuppression, are not known.

Precautions

General

It is not known whether Zenapax use will have a long-term effect on the ability of the immune system to respond to antigens first encountered during Zenapax-induced immunosuppression.

Re-administration of Zenapax after an initial course of therapy has not been studied in humans. The potential risks of such re-administration, specifically those associated with immunosuppression and/or the occurrence of anaphylaxis/anaphylactoid reactions, are not known.

Drug Interactions

The following medications have been administered with Zenapax in clinical trials in renal allograft patients with no incremental increase in adverse reactions: cyclosporine, mycophenolate mofetil, ganciclovir, acyclovir, azathioprine, and corticosteroids. Very limited experience exists in these patients with the use of Zenapax concomitantly with tacrolimus, muromonab-CD3, antithymocyte globulin, and anti-lymphocyte globulin.

In renal allograft recipients (n=50) treated with Zenapax and mycophenolate mofetil, no pharmacokinetic interaction between Zenapax and mycophenolic acid, the active metabolite of mycophenolate mofetil, was observed.

However, in a large clinical study in cardiac transplant recipients (n=434), the use of Zenapax as part of an immunosuppression regimen including cyclosporine, mycophenolate mofetil, and corticosteroids was associated with an increase in mortality, particularly in patients receiving concomitant anti-lymphocyte antibody therapy and in patients who developed severe infections (see WARNINGS and ADVERSE REACTIONS: Incidence of Infectious Episodes).

Carcinogenesis, Mutagenesis and Impairment of Fertility

Long-term studies to evaluate the carcinogenic potential of Zenapax have not been performed. Zenapax was not genotoxic in the Ames or the V79 chromosomal aberration assays, with or without metabolic activation. The effect of Zenapax on fertility is not known, because animal reproduction studies have not been conducted with Zenapax (see WARNINGS and ADVERSE REACTIONS).

Pregnancy

Pregnancy Category C: A preclinical developmental toxicity study with Zenapax has shown an increased risk of early prenatal loss in cynomolgus monkeys compared to placebo. However, the clinical experience of Zenapax exposed pregnancies is still limited. In general, IgG molecules are known to cross the placental barrier. Zenapax should not be used in pregnant women unless the potential benefit justifies the potential risk to the fetus. Women of childbearing potential should use effective contraception before beginning Zenapax therapy, during therapy, and for 4 months after completion of Zenapax therapy.

Nursing Mothers

It is not known whether Zenapax is excreted in human milk. However, in preclinical developmental toxicity studies with Zenapax, four out of seven lactating cynomolgus monkeys given a 5-10 fold multiple (10mg/kg) of the normal human dose were found to secrete very low levels of Zenapax (0.17 – 0.28% of maternal serum levels) in breast milk. Because many drugs are excreted in human milk, including human antibodies, and because of the potential for adverse reactions, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Zenapax have been established in pediatric patients from 11 months to 17 years of age. Use of Zenapax in this age group is supported by evidence from adequate and well-controlled studies of Zenapax in adults with additional pediatric pharmacokinetic data (see CLINICAL PHARMACOLOGY). Data from the pediatric pharmacokinetic study were also analyzed for efficacy, immunogenicity and safety. In an open-label study, 60 pediatric renal transplant recipients [median age of 10 years] received standard immunosuppressive agents in addition to a regimen of Zenapax administered at a dose of 1.0 mg/kg at intervals of 14 days for a total of 5 doses, starting immediately before transplantation. In this study, the combined incidence of biopsy-proven and clinically presumptive acute rejection at 1 year posttransplant was 17% (10/60). Patient and graft survival at 1 year posttransplant were 100% and 96.7%, respectively. The incidence of anti-daclizumab antibodies (34%) observed in the first 3 months posttransplant was higher than the incidence previously observed in adult patients (14%) (see ADVERSE REACTIONS: Immunogenicity).

The safety profile of Zenapax in pediatric transplant patients was shown to be comparable with that in adult transplant patients with the exception of the following adverse events, which occurred more frequently in pediatric patients (>15% difference in incidence): diarrhea, post-operative pain, fever, vomiting, aggravated hypertension, pruritus, and infections of the upper respiratory tract and urinary tract.

It is not known whether the immune response to vaccines, infection, and other antigenic stimuli administered or encountered during Zenapax therapy is impaired or whether such response will remain impaired after Zenapax therapy.

Also see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.

Geriatric Use

Clinical studies of Zenapax did not include sufficient numbers of subjects age 65 and older to determine whether they respond differently from younger subjects. Caution must be used in giving immunosuppressive drugs to elderly patients.

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug. Rates observed in clinical studies may not reflect those observed in clinical practice. Adverse reaction information obtained in clinical trials does, however, provide a basis for identifying adverse events that appear to be related to drug use and for approximating the rate of occurrence.

The safety of Zenapax was determined in four clinical studies of renal allograft rejection, three of which were randomized controlled clinical trials, in 629 patients receiving renal allografts of whom 336 received Zenapax and 293 received placebo. All patients received concomitant cyclosporine and corticosteroids. In these clinical trials, Zenapax did not appear to alter the pattern, frequency or severity of known major toxicities associated with the use of immunosuppressive drugs.

The use of Zenapax was associated with a higher incidence of mortality when compared to placebo in a large (n=434) randomized controlled study of patients receiving cardiac transplants (see WARNINGS and Incidence of Infectious Episodes).

Adverse events were reported by 95% of the patients in the placebo-treated group and 96% of the patients in the group treated with Zenapax. The proportion of patients prematurely withdrawn from the combined studies because of adverse events was 8.5% in the placebo-treated group and 8.6% in the group treated with Zenapax.

Zenapax did not increase the number of serious adverse events observed compared with placebo. The most frequently reported adverse events were gastrointestinal disorders, which were reported with equal frequency in Zenapax- (67%) and placebo-treated (68%) patient groups.

The incidence and types of adverse events were similar in both placebo-treated patients and patients treated with Zenapax. The following adverse events occurred in ≥5% of patients treated with Zenapax. These events included: Gastrointestinal System: constipation, nausea, diarrhea, vomiting, abdominal pain, pyrosis, dyspepsia, abdominal distention, epigastric pain not food-related; Metabolic and Nutritional: edema extremities, edema; Central and Peripheral Nervous System: tremor, headache, dizziness; Urinary System: oliguria, dysuria, renal tubular necrosis; Body as a Whole - General: posttraumatic pain, chest pain, fever, pain, fatigue; Autonomic Nervous System: hypertension, hypotension, aggravated hypertension; Respiratory System: dyspnea, pulmonary edema, coughing; Skin and Appendages: impaired wound healing without infection, acne; Psychiatric: insomnia; Musculoskeletal System: musculoskeletal pain, back pain; Heart Rate and Rhythm: tachycardia; Vascular Extracardiac: thrombosis; Platelet, Bleeding and Clotting Disorders: bleeding; Hemic and Lymphatic: lymphocele.

The following adverse events occurred in <5% and ≥2% of patients treated with Zenapax. These included: Gastrointestinal System: flatulence, gastritis, hemorrhoids; Metabolic and Nutritional: fluid overload, diabetes mellitus, dehydration; Urinary System: renal damage, hydronephrosis, urinary tract bleeding, urinary tract disorder, renal insufficiency; Body as a Whole - General: shivering, generalized weakness; Central and Peripheral Nervous System: urinary retention, leg cramps, prickly sensation; Respiratory System: atelectasis, congestion, pharyngitis, rhinitis, hypoxia, rales, abnormal breath sounds, pleural effusion; Skin and Appendages: pruritus, hirsutism, rash, night sweats, increased sweating; Psychiatric: depression, anxiety; Musculoskeletal System: arthralgia, myalgia; Vision: vision blurred; Application Site: application site reaction.

Incidence of Malignancies

One and 3 years posttransplant, the incidence of malignancies was 2.7% and 7.8%, respectively, in the placebo group compared with 1.5% and 6.4%, respectively, in the Zenapax group. Addition of Zenapax did not increase the number of posttransplant lymphomas up to 3 years posttransplant. Lymphomas occurred at a frequency of ≤1.5% in both placebo-treated and Zenapax-treated groups.

Hyperglycemia

No differences in abnormal hematologic or chemical laboratory test results were seen between groups treated with placebo or Zenapax with the exception of fasting blood glucose. Fasting blood glucose was measured in a small number of patients treated with placebo or Zenapax. A total of 16% (10 of 64 patients) of placebo-treated and 32% (28 of 88 patients) of patients treated with Zenapax had high fasting blood glucose values. Most of these high values occurred either on the first day posttransplant when patients received high doses of corticosteroids or in patients with diabetes.

Incidence of Infectious Episodes

The overall incidence of infectious episodes, including viral infections, fungal infections, bacteremia and septicemia, and pneumonia, was not higher in patients treated with Zenapax than in placebo-treated patients in trials of renal transplantation. In a large randomized study of Zenapax used for the prevention of allograft rejection in patients receiving cardiac allografts, more patients receiving Zenapax experienced severe or fatal infections after 12 months of therapy when compared to those receiving placebo (10% vs 7%, respectively). The risks of infection or death may be increased in patients receiving concomitant anti-lymphocyte antibody therapy (see WARNINGS).

The types of infections reported in trials of renal transplantation were similar in both the Zenapax-treated and the placebo-treated groups. Cytomegalovirus infection was reported in 16% of the patients in the placebo group and 13% of the patients in the Zenapax group. One exception was cellulitis and wound infections, which occurred in 4.1% of placebo-treated patients and 8.4% of patients treated with Zenapax. At 1 year posttransplant, 7 placebo patients and 1 patient treated with Zenapax had died of an infection. At 3 years posttransplant, 8 placebo patients and 4 patients treated with Zenapax had died of infection.

Immunogenicity

Low titers of anti-idiotype antibodies to daclizumab were detected in the adult patients treated with Zenapax with an overall incidence of 14%. The incidence of anti-daclizumab antibodies observed in the pediatric patients was 34%. No antibodies that affected efficacy, safety, serum daclizumab levels or any other clinically relevant parameter examined were detected. The data reflect the percentage of patients whose test results were considered positive for antibodies to daclizumab in an ELISA assay and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to daclizumab with the incidence of antibodies to other products may be misleading.

Post-Marketing Experience

The following adverse reactions have been identified and reported during post-approval use of Zenapax (daclizumab). Because the reports of these reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.

Severe acute hypersensitivity reactions including anaphylaxis characterized by hypotension, bronchospasm, wheezing, laryngeal edema, pulmonary edema, cyanosis, hypoxia, respiratory arrest, cardiac arrhythmia, cardiac arrest, peripheral edema, loss of consciousness, fever, rash, urticaria, diaphoresis, pruritus, and/or injection site reactions, as well as cytokine release syndrome, have been reported during post-marketing experience with Zenapax. The relationship between these reactions and the development of antibodies to Zenapax is unknown.

Overdosage

There have not been any reports of overdoses with Zenapax. A maximum tolerated dose has not been determined in patients. A dose of 1.5 mg/kg has been administered to bone marrow transplant recipients without any associated adverse events.

Zenapax Dosage and Administration

Zenapax is used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. The recommended dose for Zenapax in adult and pediatric patients is 1.0 mg/kg (see PRECAUTIONS: Pediatric Use). The calculated volume of Zenapax should be mixed with 50 mL of sterile 0.9% sodium chloride solution and administered via a peripheral or central vein over a 15-minute period.

Based on the clinical trials, the standard course of Zenapax therapy is five doses. The first dose should be given no more than 24 hours before transplantation. The four remaining doses should be given at intervals of 14 days.

No dosage adjustment is necessary for patients with severe renal impairment. No dosage adjustments based on other identified covariates (age, gender, proteinuria, race) are required for renal allograft patients. No data are available for administration in patients with severe hepatic impairment.

Instructions for Administration

• Zenapax IS NOT FOR DIRECT INJECTION. The calculated volume should be diluted in 50 mL of sterile 0.9% sodium chloride solution before intravenous administration to patients. When mixing the solution, gently invert the bag in order to avoid foaming; DO NOT SHAKE.


• Parenteral drug products should be inspected visually for particulate matter and discoloration before administration. If particulate matter is present or the solution colored, do not use.


• Care must be taken to assure sterility of the prepared solution, since the drug product does not contain any antimicrobial preservative or bacteriostatic agents.


• Zenapax is a colorless solution provided as a single-use vial; any unused portion of the drug should be discarded.


• Once the infusion is prepared, it should be administered intravenously within 4 hours. If it must be held longer, it should be refrigerated between 2° to 8°C (36° to 46°F) for up to 24 hours. After 24 hours, the prepared solution should be discarded.


• No incompatibility between Zenapax and polyvinyl chloride or polyethylene bags or infusion sets has been observed. No data are available concerning the incompatibility of Zenapax with other drug substances. Other drug substances should not be added or infused simultaneously through the same intravenous line.


• Zenapax should only be administered by healthcare personnel trained in the administration of the drug who have available adequate laboratory and supportive medical resources.

How is Zenapax Supplied

Zenapax is supplied in single-use glass vials. Each vial contains 25 mg of daclizumab in 5 mL of solution (NDC 0004-0501-09). Vials should be stored between the temperatures of 2° to 8°C (36° to 46°F); do not shake or freeze. Protect undiluted solution against direct light. Diluted medication is stable for 24 hours at 4°C or for 4 hours at room temperature.

Roche Pharmaceuticals

Hoffmann-La Roche Inc.

340 Kingsland Street

Nutley, NJ07110–1199

US Govt. Lic. No. 0136

3609650 USA

27899043

Revised: September 2005

Copyright © 1999-2005 by Hoffmann-La Roche Inc. All rights reserved.

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

PRINCIPAL DISPLAY PANEL - 25 mg/5 mL Vial Label

NDC 0004-0501-09

Zenapax®

(daclizumab)

Sterile

Concentrate for

Injection

25 mg/5 mL

(5 mg/mL)

Rx only

1 Vial

(5 mL Size)

Roche

Zenapax  daclizumab  injection, solution, concentrate

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0004-0501 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength daclizumab (daclizumab) daclizumab 25 mg  in 5 mL

Inactive Ingredients Ingredient Name Strength sodium phosphate, monobasic, monohydrate   sodium phosphate, dibasic, heptahydrate   sodium chloride   polysorbate 80   hydrochloric acid   sodium hydroxide

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0004-0501-09 5 mL In 1 VIAL, SINGLE-USE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
BLA	BLA103749	12/10/1997

Labeler - Genentech, Inc. (080129000)

Establishment
Name	Address	ID/FEI	Operations
Hoffmann-La Roche Inc		002191211	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
F. Hoffmann-La Roche Ltd		482242971	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
F. Hoffmann-La Roche Ltd		485244961	MANUFACTURE

Revised: 07/2010Genentech, Inc.

More Zenapax resources

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

• Zenapax Concise Consumer Information (Cerner Multum)


• Zenapax MedFacts Consumer Leaflet (Wolters Kluwer)


• Zenapax Monograph (AHFS DI)


• Zenapax Advanced Consumer (Micromedex) - Includes Dosage Information


• Daclizumab Professional Patient Advice (Wolters Kluwer)

Compare Zenapax with other medications

• Organ Transplant, Rejection Prophylaxis

Texacort

Generic Name: hydrocortisone (Topical application route)

hye-droe-KOR-ti-sone

Commonly used brand name(s)

In the U.S.

• Ala-Cort


• Ala-Scalp HP


• Anusol HC


• Aquanil HC


• Beta HC


• Caldecort


• Cetacort


• Corta-Cap


• Cortagel Extra Strength


• Cortaid


• CortAlo With Aloe


• Corticaine


• Corticool Maximum Strength


• Cortizone-10


• Cortizone-5


• Cotacort


• Delacort


• Dermarest


• Dermtex-HC


• Foille Cort


• Gly-Cort


• Hydrozone Plus


• Hytone


• Instacort-10


• Ivy Soothe


• IvyStat


• Keratol HC


• Kericort 10


• Lacticare-HC


• Locoid


• Locoid Lipocream


• Medi-Cortisone Maximum Strength


• Microcort


• Mycin Scalp


• Neutrogena T/Scalp


• NuCort


• Nupercainal HC


• Nutracort


• Pandel


• Pediaderm HC Kit


• Preparation H Hydrocortisone


• Proctocream-HC


• Recort Plus


• Sarnol-HC Maximum Strength


• Scalacort


• Scalpcort


• Summer's Eve Specialcare


• Texacort


• Therasoft Anti-Itch & Dermatitis


• U-Cort


• Westcort

In Canada

• Barriere-Hc


• Cortate


• Cort-Eze


• Cortoderm Mild Ointment


• Cortoderm Regular Ointment


• Emo-Cort


• Emo-Cort Scalp Solution


• Hydrocortisone Cream


• Novo-Hydrocort


• Novo-Hydrocort Cream


• Prevex Hc


• Sarna Hc

Available Dosage Forms:

• Solution


• Cream


• Spray


• Lotion


• Ointment


• Pad


• Liquid


• Gel/Jelly


• Kit


• Foam


• Stick


• Paste

Therapeutic Class: Corticosteroid, Weak

Pharmacologic Class: Adrenal Glucocorticoid

Uses For Texacort

Hydrocortisone topical is used to help relieve redness, itching, swelling, or other discomfort caused by skin conditions. This medicine is a corticosteroid (cortisone-like medicine or steroid).

This medicine is available both over-the-counter (OTC) and with your doctor's prescription.

Before Using Texacort

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 hydrocortisone topical in the pediatric population. However, because of this medicine's toxicity, it should be used with caution. Children may absorb large amounts through the skin, which can cause serious side effects. If your child is using this medicine, follow your doctor's instructions very carefully.

Geriatric

No information is available on the relationship of age to the effects of hydrocortisone topical in geriatric patients.

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:

• Cushing's syndrome (adrenal gland disorder) or


• Diabetes or


• Hyperglycemia (high blood sugar) or


• Intracranial hypertension (increased pressure in the head)—Use with caution. May make these conditions worse.

• Infection of the skin at or near the place of application or


• Large sores, broken skin, or severe skin injury at the place of application—The chance of side effects may be increased.

Proper Use of hydrocortisone

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

It is very important that you use this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. To do so may cause unwanted side effects or skin irritation.

This medicine is for use on the skin only. Do not get it in your eyes. Do not use it on skin areas that have cuts, scrapes, or burns. If it does get on these areas, rinse it off right away with water.

This medicine should only be used for skin conditions that your doctor is treating. Check with your doctor before using it for other conditions, especially if you think that a skin infection may be present. This medicine should not be used to treat certain kinds of skin infections or conditions, such as severe burns.

To use:

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


• Apply a thin layer of this medicine to the affected area of the skin. Rub it in gently.


• With the lotion, shake it well before using.


• Do not bandage or otherwise wrap the skin being treated unless directed to do so by your doctor.


• If the medicine is applied to the diaper area of an infant, do not use tight-fitting diapers or plastic pants unless directed to do so by your doctor.


• If your doctor ordered an occlusive dressing or airtight covering to be applied over the medicine, make sure you know how to apply it. Occlusive dressings increase the amount of medicine absorbed through your skin, so use them only as directed. If you have any questions about this, check with your doctor.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For redness, itching, and swelling of the skin:
  
  • For topical dosage form (cream):
    
    • Adults—Apply to the affected area of the skin two or three times per day.
    
    
    • Children—Apply to the affected area of the skin two or three times per day.
    
    
  
  
  • For topical dosage form (lotion):
    
    • Adults—Apply to the affected area of the skin two to four times per day.
    
    
    • Children—Apply to the affected area of the skin two to four times per day.
    
    
  
  
  • For topical dosage form (ointment):
    
    • Adults—Apply to the affected area of the skin three or four times per day.
    
    
    • Children—Apply to the affected area of the skin three or four times per day.
    
    
  
  
  • For topical dosage form (solution):
    
    • Adults—Apply to the affected area of the skin three or four times per day.
    
    
    • Children—Apply to the affected area of the skin three or four times per day.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

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.

Precautions While Using Texacort

It is very important that your doctor check your or your child's progress at regular visits for any unwanted effects that may be caused by this medicine.

If your or your child's symptoms do not improve within a few days, or if they become worse, check with your doctor.

Using too much of this medicine or using it for a long time may increase your risk of having adrenal gland problems. The risk is greater for children and patients who use large amounts for a long time. Talk to your doctor right away if you or your child have more than one of these symptoms while you are using this medicine: blurred vision; dizziness or fainting; a fast, irregular, or pounding heartbeat; increased thirst or urination; irritability; or unusual tiredness or weakness.

Stop using this medicine and check with your doctor right away if you or your child have a skin rash, burning, stinging, swelling, or irritation on the skin.

Do not use cosmetics or other skin care products on the treated areas.

Texacort 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 immediately if any of the following side effects occur:

Incidence not known

• Blistering, burning, crusting, dryness, or flaking of the skin


• irritation


• itching, scaling, severe redness, soreness, or swelling of the skin


• redness and scaling around the mouth


• thinning of the skin with easy bruising, especially when used on the face or where the skin folds together (e.g. between the fingers)


• thinning, weakness, or wasting away of the 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:

Incidence not known

• Acne or pimples


• burning and itching of the skin with pinhead-sized red blisters


• burning, itching, and pain in hairy areas, or pus at the root of the hair


• increased hair growth on the forehead, back, arms, and legs


• lightening of normal skin color


• lightening of treated areas of dark skin


• reddish purple lines on the arms, face, legs, trunk, or groin


• softening of the skin

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.

See also: Texacort side effects (in more detail)

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.

More Texacort resources

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Mycolog-II Cream

Nystatin and Triamcinolone Acetonide

Dosage Form: Cream

For Dermatologic Use Only

NOT FOR OPHTHALMIC USE

Mycolog-II Description

Mycolog-II Cream (Nystatin and Triamcinolone Acetonide Cream) for dermatologic use contains the antifungal agent nystatin and the synthetic corticosteroid triamcinolone acetonide.

Nystatin is a polyene antimycotic obtained from Streptomyces noursei. It is a yellow to light tan powder with a cereal-like odor, very slightly soluble in water, and slightly to sparingly soluble in alcohol. Structural formula:

Triamcinolone acetonide is designated chemically as 9-fluoro-11β, 16α, 17, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione cyclic 16, 17-acetal with acetone. The white to cream crystalline powder has a slight odor, is practically insoluble in water, and very soluble in alcohol. Structural formula:

Mycolog-II (Nystatin and Triamcinolone Acetonide Cream) is a soft, smooth, cream having a light yellow to buff color. Each gram provides 100,000 units of nystatin and 1.0 mg triamcinolone acetonide in an aqueous perfumed vanishing cream base with aluminum hydroxide concentrated wet gel, titanium dioxide, glyceryl monostearate, polyethylene glycol monostearate, simethicone, sorbic acid, propylene glycol, white petrolatum, cetearyl alcohol (and) ceteareth-20, and sorbitol solution.

Mycolog-II - Clinical Pharmacology

Nystatin

Nystatin exerts its antifungal activity against a variety of pathogenic and nonpathogenic yeasts and fungi by binding to sterols in the cell membrane. The binding process renders the cell membrane incapable of functioning as a selective barrier. Nystatin provides specific anticandidal activity to Candida (Monilia) albicans and other Candida species, but is not active against bacteria, protozoa, trichomonads, or viruses.

Nystatin is not absorbed from intact skin or mucous membranes.

Triamcinolone Acetonide

Triamcinolone acetonide is primarily effective because of its anti-inflammatory, antipruritic and vasoconstrictive actions, characteristic of the topical corticosteroid class of drugs. The pharmacologic effects of the topical corticosteroids are well-known; however, the mechanisms of their dermatologic actions are unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.

Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings (see DOSAGE AND ADMINISTRATION).

Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids (see DOSAGE AND ADMINISTRATION).

Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.

Nystatin and Triamcinolone Acetonide

During clinical studies of mild to severe manifestations of cutaneous candidiasis, patients treated with MYCOLOG II (Nystatin and Triamcinolone Acetonide Cream) showed a faster and more pronounced clearing of erythema and pruritus than patients treated with nystatin or triamcinolone acetonide alone.

Indications and Usage for Mycolog-II

Mycolog-II (Nystatin and Triamcinolone Acetonide Cream) is indicated for the treatment of cutaneous candidiasis; it has been demonstrated that the nystatin-steroid combination provides greater benefit than the nystatin component alone during the first few days of treatment.

Contraindications

This preparation is contraindicated in those patients with a history of hypersensitivity to any of its components.

Precautions

General

Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria in some patients.

Conditions that augment systemic absorption include application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings (see DOSAGE AND ADMINISTRATION).

Therefore, patients receiving a large dose of any potent topical steroid applied to large surface area should be evaluated periodically for evidence of HPA axis suppression by using the urinary free cortisol and ACTH stimulation tests, and for impairment of thermal homeostasis. If HPA axis suppression or elevation of the body temperature occurs, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid.

Recovery of HPA axis function and thermal homeostasis are generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids.

Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity (see PRECAUTIONS, Pediatric Use).

If irritation or hypersensitivity develops with the combination nystatin and triamcinolone acetonide, treatment should be discontinued and appropriate therapy instituted.

Information for the Patient

Patients using this medication should receive the following information and instructions:

1. This medication is to be used as directed by the physician. It is for dermatologic use only. Avoid contact with the eyes.


2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed.


3. The treated skin area should not be bandaged or otherwise covered or wrapped as to be occluded (see DOSAGE AND ADMINISTRATION).


4. Patients should report any signs of local adverse reactions.


5. When using this medication in the inguinal area, patients should be advised to apply the cream sparingly and to wear loosely fitting clothing.


6. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings.


7. Patients should be advised on preventive measures to avoid reinfection.

Laboratory Test

If there is a lack of therapeutic response, appropriate microbiological studies (e.g., KOH smears and/or cultures) should be repeated to confirm the diagnosis and rule out other pathogens, before instituting another course of therapy.

A urinary free cortisol test and ACTH stimulation test may be helpful in evaluating hypothalamic-pituitary-adrenal (HPA) axis suppression due to corticosteroid.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies have not been performed to evaluate carcinogenic or mutagenic potential, or possible impairment of fertility in males or females.

Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no teratogenic studies with combined nystatin and triamcinolone acetonide. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Therefore, any topical corticosteroid preparation should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Topical preparations containing corticosteroids should not be used extensively on pregnant patients, in large amounts, or for prolonged periods of time.

Nursing Mothers

It is not known whether any component of this preparation is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised during use of this preparation by a nursing woman.

Pediatric Use

In clinical studies of limited number number of pediatric patients ranging in age from two months through 12 years, Mycolog-II cleared or significantly ameliorated the disease state in most patients.

Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing’s syndrome than mature patients because of a larger skin surface area to body weight ratio.

HPA axis suppression, Cushing’s syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Chronic corticosteroid therapy may interfere with the growth and development of children.

Adverse Reactions

A single case (approximately one percent of patients studied) of acneform eruption occurred with use of combined nystatin and triamcinolone acetonide in clinical studies.

Nystatin is virtually nontoxic and nonsensitizing and is well tolerated by all age groups, even during prolonged use. Rarely, irritation may occur.

The following local adverse reactions are reported infrequently with topical corticosteroids (reactions are listed in an approximate decreasing order of occurrence): burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, and miliaria.

Overdosage

Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS, General); however, acute overdosage and serious adverse effects with dermatologic use are unlikely.

Mycolog-II Dosage and Administration

Mycolog-II Cream (Nystatin and Triamcinolone Acetonide Cream) is usually applied to the affected areas twice daily in the morning and evening by gently and thoroughly massaging the preparation into the skin. The cream should be discontinued if symptoms persist after 25 days of therapy (see PRECAUTIONS, Laboratory Tests).

Mycolog II Cream should not be used with occlusive dressings.

How is Mycolog-II Supplied

Mycolog-II Cream (Nystatin and Triamcinolone Acetonide Cream USP) is supplied in 15 g (NDC 0003-0566-30), 30 g (NDC 0003-0566-60), and 60 g (NDC 0003-0566-65) tubes and 120 g (NDC 0003-0566-50) jars.

Storage

Store at room temperature; avoid freezing.

APOTHECON®

A Bristol-Myers Squibb Company

Princeton, NJ 08540 USA

J4-019D

February 1993

Mycolog-II  nystatin and triamcinolone acetonide  cream

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0003-0566 Route of Administration TOPICAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength nystatin (nystatin) Active 100000 UNITS  In 1 GRAM triamcinolone acetonide (triamcinolone) Active 1 MILLIGRAM  In 1 GRAM aluminum hydroxide concentrated wet gel Inactive   titanium dioxide Inactive   glyceryl monostearate Inactive   polyethylene glycol monostearate Inactive   simethicone Inactive   sorbic acid Inactive   propylene glycol Inactive   white petrolatum Inactive   cetearyl alcohol (and) ceteareth-20 Inactive   sorbitol solution Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0003-0566-30 15 g (GRAM) In 1 TUBE None 2 0003-0566-60 30 g (GRAM) In 1 TUBE None 3 0003-0566-65 60 g (GRAM) In 1 TUBE None 4 0003-0566-50 120 g (GRAM) In 1 JAR None

Revised: 09/2006Bristol-Myers Squibb Company

More Mycolog-II resources

• Mycolog-II Side Effects (in more detail)
• Mycolog-II Use in Pregnancy & Breastfeeding
• Mycolog-II Drug Interactions
• 1 Review for Mycolog-II - Add your own review/rating

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• Cutaneous Candidiasis

Guna-Diur

Dosage Form: oral solution / drops
GUNA®-DIUR

1. INDICATIONS AND USAGE

1.1.    Essential Hypertension (use with GUNA-MALE/FEM)

1.2.    Fluid retention (use with GUNA-PMS)

1.3.    Temporary weight gain (use with GUNA-MATRIX and GUNA-LYMPHO)

1.4.    Lymphedema (use with GUNA-LYMPHO)

1.5.    Tissue swelling

Administration may vary according to individual needs.

GUNA®-DIUR may be used together with other homeopathic medications

2. DOSAGE AND ADMINISTRATION

The usual initial dose of GUNA®-DIUR is:


Adults and children 12 years and older                20 drops in a little water, 2 times per day

Children  between 12 years and 6 years of age    10 drops in a little water, 2 times per day

Children under 6 years                                         5 drops in a glass of water, 2 times per day


For an average of two months. If response is not satisfactory, add other products as suggested by your health care professional.

3. DOSAGE FORMS AND STRENGTHS

3.1.    30 ml Bottle dropper.

3.2.    Each ingredient is attenuated according to the procedures stated in the Homeopathic Pharmacopeia of the United States. Amiloride 4x, Apis Mellifica 2x, Berberis Vulgaris T, Hydrochlorothiazide 4x, Hypophysis 12x, Mouse-Ear Hawkweed T, Solidago Virgaurea T, Spironolactone 4x.

Inactive Ingredient: Ethylic Alcohol 30%

4. CONTRAINDICATIONS

4.1.    There is no history of hypersensitivity to GUNA®-DIUR. However patients with a known hypersensitivity to any GUNA®-DIUR ingredient should consult a physician prior to taking the medication

5. WARNINGS AND PRECAUTIONS

5.1.    GUNA®-DIUR is contraindicated in patients with anuria and in patients with a history of hypersensitivity to Spironolactone, Amiloride, or Hydrocholorthiazide.

5.2.    Use with caution in patients taking diuretic medications.

6. ADVERSE REACTIONS

6.1.    None known (see CONTRAINDICATIONS for hypersensitivity information).

7. DRUG INTERACTIONS

7.1.    None Known

8. USE IN SPECIFIC POPULATIONS

8.1.    Pregnancy:  Pregnancy  category  C.  Animal reproduction studies have not been conducted with GUNA®-DIUR.  GUNA®- DIUR should not be given to a pregnant woman. 

8.2.    Nursing mothers:    It is not known whether any of the ingredients in GUNA®- DIUR are secreted in human milk.  However, since many drugs are secreted in human milk, caution should be exercised when GUNA®- DIUR is administered to a nursing woman.

8.3.    Pediatric use: See DOSAGE AND AMINISTRATION.

8.4.    Geriatric use: No restrictions.

9. DRUG ABUSE AND DEPENDENCE

9.1.    No Known.

10. OVERDOSAGE

10.1.    No Known.

11. DESCRIPTION

Guna-Diur is a biochemical homeopathic medication indicated for the treatment of fluid retention, swelling, essential hypertension, lymphedema, and related discomforts.

12. CLINICAL PHARMACOLOGY

12.1.    Mechanism of Action

The active ingredients in GUNA®- DIUR are simple biochemical compounds.   The exact mechanism of action is unknown; however, due to the homeopathic nature of the active ingredients, receptors may be activated by feedback regulation. 

12.2.    Pharmacodynamics

The physiological effects of GUNA®-DIUR are due to the action of the ingredients, as described in the Homeopathic Materia Medica.

In Homeopathy there is no direct relationship between dose and effect, but rather there is a relationship between attenuation and balancing effect on biochemical pathways.

In GUNA®-DIUR the attenuation of each ingredient has been selected according to Arndt-Schulz Principle (inverted effect law). The attenuation of the physiological ingredients promotes membrane receptor feedback in order to normalize altered biological pathways. In Addition the attenuation technique activates the low dilutions and stabilizes clinical activity of the compound.

12.3.    Pharmacokinetics

The homeopathic attenuation provides complete bioavailability of the active ingredients.

13. NONCLINICAL TOXICOLOGY

13.1.    GUNA®-DIUR has no level of toxicity due to the attenuation of the ingredients

14. CLINICAL STUDIES

14.1.    GUNA®-DIUR formulation is based on classical Homeopathy and each ingredient has been selected according to its description in the Homeopathic Materia Medica

15. REFERENCES

15.1.    H.H. Reckeweg. Homeopathic Materia Medica.  Aurelia Verlag.

15.2.    Boericke,  William,  Materia  Medica  with  Reperatory,  1927,  ninth edition

16. HOW SUPPLIED/STORAGE AND HANDLING

16.1.    NDC  17089-260-18   Oral  Solution/Drops 30 mL

16.2.    Store at room temperature, 20-25°C (68-77° F). Avoid  freezing  and  excessive  heat.

17. PATIENT COUNSELING INFORMATION

17.1.    Patients should be informed about Homeopathy and the main differences with conventional clinical approaches.

PACKAGE LABEL

Guna-Diur  amiloride - apis mellifera - berberis vulgaris fruit - hieracium pilosella flowering top - hydrochlorothiazide - solidago virgaurea flowering top - spironolactone - sus scrofa pituitary gland -   solution/ drops

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 17089-260 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AMILORIDE (AMILORIDE) AMILORIDE 4 [hp_X]  in 30 mL APIS MELLIFERA (APIS MELLIFERA) APIS MELLIFERA 2 [hp_X]  in 30 mL BERBERIS VULGARIS FRUIT (BERBERIS VULGARIS FRUIT) BERBERIS VULGARIS FRUIT 0.3 mL  in 30 mL HYDROCHLOROTHIAZIDE (HYDROCHLOROTHIAZIDE) HYDROCHLOROTHIAZIDE 4 [hp_X]  in 30 mL SUS SCROFA PITUITARY GLAND (SUS SCROFA PITUITARY GLAND) SUS SCROFA PITUITARY GLAND 12 [hp_X]  in 30 mL HIERACIUM PILOSELLA FLOWERING TOP (HIERACIUM PILOSELLA FLOWERING TOP) HIERACIUM PILOSELLA FLOWERING TOP 0.3 mL  in 30 mL SOLIDAGO VIRGAUREA FLOWERING TOP (SOLIDAGO VIRGAUREA FLOWERING TOP) SOLIDAGO VIRGAUREA FLOWERING TOP 0.3 mL  in 30 mL SPIRONOLACTONE (SPIRONOLACTONE) SPIRONOLACTONE 4 [hp_X]  in 30 mL

Inactive Ingredients Ingredient Name Strength ALCOHOL 9 mL  in 30 mL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 17089-260-18 1 BOTTLE In 1 BOX contains a BOTTLE, DROPPER 1 30 mL In 1 BOTTLE, DROPPER This package is contained within the BOX (17089-260-18)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved homeopathic		05/23/2006

Labeler - Guna spa (430538264)

Establishment
Name	Address	ID/FEI	Operations
Guna spa		430538264	manufacture

Revised: 06/2010Guna spa

Lamisil AT Athletes Foot

Generic Name: terbinafine topical (ter BIN a feen TOP i kal)

Brand Names: Athlete's Foot Cream, LamISIL AT, LamISIL AT Athletes Foot, LamISIL AT Jock Itch, LamISIL Topical

What is Lamisil AT Athletes Foot (terbinafine topical)?

Terbinafine is an antifungal medication. Terbinafine topical prevents fungus from growing on the skin.

Terbinafine topical (for the skin) is used to treat skin infections such as athlete's foot, jock itch, and ringworm infections.

Terbinafine topical may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Lamisil AT Athletes Foot (terbinafine topical)?

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to.

Avoid getting this medication in your mouth or eyes.

What should I discuss with my healthcare provider before using Lamisil AT Athletes Foot (terbinafine topical)?

You should not use this medication if you are allergic to it. It is not known whether terbinafine topical will be harmful to an unborn baby. Do not use terbinafine topical without first talking to your doctor if you are pregnant. It is not known whether terbinafine topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use Lamisil AT Athletes Foot (terbinafine topical)?

Use this medication exactly as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended. Follow the directions on your prescription label.

Wash your hands before and after using this medication.

Clean and dry the affected area. Apply the medication as directed.

Use this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.

For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after a few weeks of treatment.

Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to.

Store terbinafine topical at room temperature away from moisture and heat.

What happens if I miss a dose?

Apply the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to use the medicine and skip the missed dose. Do not apply extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

An overdose of terbinafine topical is not likely to cause life-threatening symptoms.

What should I avoid while using Lamisil AT Athletes Foot (terbinafine topical)?

Avoid getting this medication in your mouth or eyes. If it does get into any of these areas, rinse with water.

Avoid using other medications on the areas you treat with terbinafine topical unless your doctor has told you to.

Avoid wearing tight-fitting, synthetic clothing that doesn't allow air circulation. Wear loose-fitting clothing made of cotton and other natural fibers until your infection is healed.

Lamisil AT Athletes Foot (terbinafine topical) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using terbinafine topical and call your doctor at once if you have a serious side effect such as severe blistering, itching, redness, peeling, dryness, or irritation of the skin.

Less serious side effects are more likely, and you may have none at all.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Lamisil AT Athletes Foot (terbinafine topical)?

It is not likely that other drugs you take orally or inject will have an effect on topically applied terbinafine topical. But many drugs can interact with each other. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

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• Lamisil AT Athletes Foot Support Group
• 4 Reviews for Lamisil AT Athletes Foot - Add your own review/rating

• Lamisil AT Prescribing Information (FDA)


• Lamisil AT Topical Advanced Consumer (Micromedex) - Includes Dosage Information


• Lamisil AT Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• Lamisil AT Jock Itch Prescribing Information (FDA)

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Where can I get more information?

• Your pharmacist has additional information about terbinafine topical written for health professionals that you may read.

See also: Lamisil AT Athletes Foot side effects (in more detail)

Tylenol with Codeine

acetaminophen and codeine phosphate

Dosage Form: tablets
TYLENOL®

with Codeine

CIII

(acetaminophen and codeine phosphate) tablets

HEPATOTOXICITY

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product (see WARNINGS).

Tylenol with Codeine Description

TYLENOL® with Codeine is supplied in tablet form for oral administration.

Acetaminophen, 4'-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula:

C8 H9 NO2       M.W. 151.16

Codeine phosphate, 7,8-didehydro-4, 5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate, a white crystalline powder, is a narcotic analgesic and antitussive. It has the following structural formula:

C18H21NO3•H3PO4•1/2 H2O       M.W. 406.37

Each tablet contains:

Acetaminophen	300 mg
No. 3 Codeine Phosphate	30 mg
(Warning: May be habit forming)
Acetaminophen	300 mg
No. 4 Codeine Phosphate	60 mg
(Warning: May be habit forming)

In addition, each tablet contains the following inactive ingredients:

TYLENOL® with Codeine No. 3 contains powdered cellulose, magnesium stearate, sodium metabisulfite1, pregelatinized starch (corn), and modified starch (corn).

TYLENOL® with Codeine No. 4 contains powdered cellulose, magnesium stearate, sodium metabisulfite1, pregelatinized starch (corn), and corn starch.

1

See WARNINGS

Tylenol with Codeine - Clinical Pharmacology

This product combines the analgesic effects of a centrally acting analgesic, codeine, with a peripherally acting analgesic, acetaminophen.

Pharmacokinetics

The behavior of the individual components is described below.

Codeine

Codeine is rapidly absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen, and kidney. Codeine crosses the blood-brain barrier and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain; however, codeine is not bound to plasma proteins and does not accumulate in body tissues.

The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces.

At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours.

Acetaminophen

Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug.

Indications and Usage for Tylenol with Codeine

TYLENOL® with Codeine (acetaminophen and codeine phosphate) Tablets are indicated for the relief of mild to moderately severe pain.

Contraindications

This product should not be administered to patients who have previously exhibited hypersensitivity to codeine or acetaminophen.

Warnings

Hepatotoxicity

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products (see Boxed Warning).

The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.

Hypersensitivity/Anaphylaxis

There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue TYLENOL® with Codeine immediately and seek medical care if they experience these symptoms. Do not prescribe TYLENOL® with Codeine for patients with acetaminophen allergy.

Head Injuries

In the presence of head injury or other intracranial lesions, the respiratory-depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other CNS-depressant effects, such as drowsiness, that may further obscure the clinical course of the patients with head injuries.

Acute Abdominal Conditions

Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions.

Abuse Potential

Codeine is habit forming and potentially abusable. Consequently, the extended use of this product is not recommended.

Sulfite Sensitivity

TYLENOL® with Codeine (acetaminophen and codeine phosphate) Tablets contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Precautions

General

TYLENOL® with Codeine (acetaminophen and codeine phosphate) Tablets should be prescribed with caution in certain special-risk patients, such as the elderly or debilitated, and those with severe impairment of renal or hepatic function, head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison's disease, or prostatic hypertrophy.

Ultra-Rapid Metabolizers of Codeine

Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2×2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5% to 1% in Chinese and Japanese, 0.5% to 1% in Hispanics, 1% to 10% in Caucasians, 3% in African Americans, and 16% to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups.

When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and inform their patients about these risks and the signs of morphine overdose (see PRECAUTIONS – Nursing Mothers).

Information for Patients/Caregivers

• Do not take TYLENOL® with Codeine if you are allergic to any of its ingredients.


• If you develop signs of allergy such as a rash or difficulty breathing, stop taking TYLENOL® with Codeine and contact your healthcare provider immediately.


• Do not take more than 4,000 milligrams of acetaminophen per day. Call your healthcare provider if you took more than the recommended dose.


• Codeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Avoid such tasks while taking this product.


• Alcohol and other CNS depressants may produce an additive CNS depression when taken with this combination product. Avoid drinking alcohol or taking other CNS depressants when you are taking Tylenol with Codeine.


• Codeine may be habit forming. Take this drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.


• Some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine, which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer.


• Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. If you are a nursing mother, watch for signs of morphine toxicity in your infant, including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Talk to your baby's doctor immediately if you notice these signs. If you cannot reach the doctor right away, take your baby to an emergency room or call 911 (or local emergency services).

Laboratory Tests

In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests.

Drug Interactions

This drug may enhance the effects of other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other CNS depressants, causing increased CNS depression.

Drug/Laboratory Test Interactions

Codeine may increase serum amylase levels.

Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No adequate studies have been conducted in animals to determine whether acetaminophen and codeine have a potential for carcinogenesis or mutagenesis. No adequate studies have been conducted in animals to determine whether acetaminophen has a potential for impairment of fertility.

Acetaminophen and codeine have been found to have no mutagenic potential using the Ames Salmonella-Microsomal Activation test, the Basc test on Drosophila germ cells, and the Micronucleus test on mouse bone marrow.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Codeine

A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120 mg/kg level, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In another study a single 100 mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring.

There are no adequate and well-controlled studies in pregnant women. TYLENOL® with Codeine (acetaminophen and codeine phosphate) Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. These signs usually appear during the first few days of life.

Labor and Delivery

Narcotic analgesics cross the placental barrier. The closer to delivery and the larger the dose used, the greater the possibility of respiratory depression in the newborn. Narcotic analgesics should be avoided during labor if delivery of a premature infant is anticipated. If the mother has received narcotic analgesics during labor, newborn infants should be observed closely for signs of respiratory depression. Resuscitation may be required (see OVERDOSAGE). The effect of codeine, if any, on the later growth, development, and functional maturation of the child is unknown.

Nursing Mothers

Acetaminophen is excreted in breast milk in small amounts, but the significance of its effect on nursing infants is not known. Because of the potential for serious adverse reactions in nursing infants from acetaminophen, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5% to 1% in Chinese and Japanese, 0.5% to 1% in Hispanics, 1% to 10% in Caucasians, 3% in African Americans, and 16% to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups.

The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine-containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding (see PRECAUTIONS – General, Ultra-Rapid Metabolizers of Codeine).

Adverse Reactions

The most frequently observed adverse reactions include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea and vomiting. These effects seem to be more prominent in ambulatory than in nonambulatory patients, and some of these adverse reactions may be alleviated if the patient lies down.

Other adverse reactions include allergic reactions, euphoria, dysphoria, constipation, abdominal pain, pruritus, rash, thrombocytopenia, and agranulocytosis.

At higher doses, codeine has most of the disadvantages of morphine including respiratory depression.

Drug Abuse and Dependence

Controlled Substance

TYLENOL® with Codeine (acetaminophen and codeine phosphate) Tablets are classified as a Schedule III controlled substance.

Abuse and Dependence

Codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused. Psychological dependence, physical dependence, and tolerance may develop upon repeated administration and it should be prescribed and administered with the same degree of caution appropriate to the use of other oral narcotic medications.

Overdosage

Following an acute overdosage, toxicity may result from codeine or acetaminophen.

Signs and Symptoms

Toxicity from codeine poisoning includes the opioid triad of pinpoint pupils, depression of respiration, and loss of consciousness. Convulsions may occur.

In acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur.

Early symptoms following a potentially hepatotoxic overdose may include nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.

Treatment

A single or multiple drug overdose with acetaminophen and codeine is a potentially lethal polydrug overdose and consultation with a regional poison control center is recommended.

Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption.

Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to overdosage or unusual sensitivity to codeine, parenteral naloxone is a specific and effective antagonist.

Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 or more hours after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose-dependent and occurs early in the course of intoxication.

Tylenol with Codeine Dosage and Administration

Dosage should be adjusted according to severity of pain and response of the patient.

The usual adult dosage is:

	Single Doses (Range)	Maximum 24-Hour Dose
Codeine Phosphate	15 mg to 60 mg	360 mg
Acetaminophen	300 mg to 1,000 mg	4,000 mg

Doses may be repeated up to every 4 hours.

The prescriber must determine the number of tablets per dose, and the maximum number of tablets per 24 hours, based upon the above dosage guidance. This information should be conveyed in the prescription.

It should be kept in mind, however, that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. Adult doses of codeine higher than 60 mg fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of undesirable side effects. Equivalently high doses in children would have similar effects.

How is Tylenol with Codeine Supplied

TYLENOL® with Codeine (acetaminophen and codeine phosphate) Tablets are white, round, flat-faced, beveled-edged tablet, imprinted "McNEIL" on one side and "TYLENOL CODEINE" and either "3" or "4" on the other side and are supplied as follows:

TYLENOL® with Codeine No. 3 bottle of 100 tablets – NDC 50458-513-60

TYLENOL® with Codeine No. 3 bottle of 1000 tablets – NDC 50458-513-80

TYLENOL® with Codeine No. 4 bottle of 100 tablets – NDC 50458-515-60

TYLENOL® with Codeine No. 4 bottle of 500 tablets – NDC 50458-515-70

Store TYLENOL® with Codeine Tablets at 20° to 25°C (68° to 77°F). (See USP Controlled Room Temperature.)

Dispense in tight, light-resistant container as defined in the official compendium.

Manufactured by:

Janssen Ortho, LLC

Gurabo, Puerto Rico 00778

Manufactured for:

PriCara®

Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.

Raritan, New Jersey 08869

10186601

Revised September 2011

© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2000

PRINCIPAL DISPLAY PANEL - 100 Tablet Bottle Label

NDC 50458-513-60

CIII

100 tablets

Tylenol®

with codeine

ACETAMINOPHEN AND

CODEINE PHOSPHATE

TABLETS No.3

Each tablet contains:

codeine phosphate 30 mg

acetaminophen 300 mg

Rx only.

PriCara®

Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.

PRINCIPAL DISPLAY PANEL - 100 Tablet Bottle Label

NDC 50458-515-60

CIII

100 tablets

Tylenol®

with codeine

ACETAMINOPHEN AND

CODEINE PHOSPHATE

TABLETS No.4

Each tablet contains:

codeine phosphate 60 mg

acetaminophen 300 mg

Rx only.

PriCara®

Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc.

Tylenol with Codeine  acetaminophen and codeine phosphate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 50458-513 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength acetaminophen (acetaminophen) acetaminophen 300 mg codeine phosphate (codeine) codeine phosphate 30 mg

Inactive Ingredients Ingredient Name Strength powdered cellulose   magnesium stearate   sodium metabisulfite   starch, corn

Product Characteristics Color WHITE Score no score Shape ROUND Size 11mm Flavor Imprint Code McNEIL;TYLENOL;CODEINE;3 Contains

Packaging # NDC Package Description Multilevel Packaging 1 50458-513-60 100 TABLET In 1 BOTTLE None 2 50458-513-80 1000 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA085055	08/17/1977

Tylenol with Codeine  acetaminophen and codeine phosphate  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 50458-515 Route of Administration ORAL DEA Schedule CIII

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength acetaminophen (acetaminophen) acetaminophen 300 mg codeine phosphate (codeine) codeine phosphate 60 mg

Inactive Ingredients Ingredient Name Strength powdered cellulose   magnesium stearate   sodium metabisulfite   starch, corn

Product Characteristics Color WHITE Score no score Shape ROUND Size 11mm Flavor Imprint Code McNEIL;TYLENOL;CODEINE;4 Contains

Packaging # NDC Package Description Multilevel Packaging 1 50458-515-60 100 TABLET In 1 BOTTLE None 2 50458-515-70 500 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA085055	08/17/1977

Labeler - Janssen Pharmaceuticals, Inc. (063137772)

Establishment
Name	Address	ID/FEI	Operations
Janssen Ortho LLC		062191882	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Mallinckrodt Inc.		097722284	ANALYSIS, API MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Noramco Inc.		166506142	API MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Ortho-McNeil-Janssen Pharmaceuticals, Inc.		063137772	ANALYSIS

Revised: 07/2011Janssen Pharmaceuticals, Inc.

More Tylenol with Codeine resources

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• Tylenol with Codeine Dosage
• Tylenol with Codeine Use in Pregnancy & Breastfeeding
• Tylenol with Codeine Drug Interactions
• Tylenol with Codeine Support Group
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