Elidel

pimecrolimus

Dosage Form: cream
Elidel®

(pimecrolimus) Cream 1%

FOR DERMATOLOGIC USE ONLY

NOT FOR OPHTHALMIC USE

Rx only

Prescribing Information

See WARNINGS, boxed WARNING concerning long-term safety of topical calcineurin inhibitors.

Elidel Description

Elidel® (pimecrolimus) Cream 1% contains the compound pimecrolimus, the immunosuppressant 33-epichloro-derivative of the macrolactam ascomycin.

Chemically, pimecrolimus is (1R,9S,12S,13R,14S,17R, 18E,21S,23S,24R,25S,27R) - 12 - [(1E) - 2 - {(1R,3R,4S) - 4 - chloro - 3 - methoxycyclohexyl} - 1 - methylvinyl] - 17 - ethyl - 1, 14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0 4,9]octacos-18-ene-2,3,10,16-tetraone.

The compound has the empirical formula C 43H68CINO11 and the molecular weight of 810.47. The structural formula is

Pimecrolimus is a white to off-white fine crystalline powder. It is soluble in methanol and ethanol and insoluble in water.

Each gram of Elidel Cream 1% contains 10 mg of pimecrolimus in a whitish cream base of benzyl alcohol, cetyl alcohol, citric acid, mono- and di-glycerides, oleyl alcohol, propylene glycol, sodium cetostearyl sulphate, sodium hydroxide, stearyl alcohol, triglycerides, and water.

Elidel - Clinical Pharmacology

Mechanism of Action/Pharmacodynamics

The mechanism of action of pimecrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T cells. In addition, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/IgE.

Pharmacokinetics

Absorption

In adult patients (n=52) being treated for atopic dermatitis [13%-62% Body Surface Area (BSA) involvement] for periods up to a year, a maximum pimecrolimus concentration of 1.4 ng/mL was observed among those subjects with detectable blood levels. In the majority of samples in adult (91%; 1,244/1,362) subjects, blood concentrations of pimecrolimus were below 0.5 ng/mL. Data on blood levels of pimecrolimus measured in pediatric patients are described below in Special Populations, Pediatrics.

Distribution

Laboratory in vitro plasma protein binding studies using equilibrium gel filtration have shown that 99.5% of pimecrolimus in plasma is bound to proteins over the pimecrolimus concentration range of 2-100 ng/mL tested. The major fraction of pimecrolimus in plasma appears to be bound to various lipoproteins. As with other topical calcineurin inhibitors, it is not known whether pimecrolimus is absorbed into cutaneous lymphatic vessels or in regional lymph nodes.

Metabolism

Following the administration of a single oral radiolabeled dose of pimecrolimus numerous circulating O-demethylation metabolites were seen. Studies with human liver microsomes indicate that pimecrolimus is metabolized in vitro by the CYP3A sub-family of metabolizing enzymes. No evidence of skin mediated drug metabolism was identified in vivo using the minipig or in vitro using stripped human skin.

Elimination

Based on the results of the aforementioned radiolabeled study, following a single oral dose of pimecrolimus ~81% of the administered radioactivity was recovered, primarily in the feces (78.4%) as metabolites. Less than 1% of the radioactivity found in the feces was due to unchanged pimecrolimus.

Special Populations

Pediatrics

The systemic exposure to pimecrolimus from Elidel® (pimecrolimus) Cream 1% was investigated in 28 pediatric patients with atopic dermatitis (20%-80% BSA involvement) between the ages of 8 months-14 yrs. Following twice daily application for three weeks, blood concentrations of pimecrolimus were <2 ng/mL with 60% (96/161) of the blood samples having blood concentration below the limit of quantification (0.5 ng/mL). However, the children (23 children out of the total 28 children investigated) had at least one detectable blood level as compared to the adults (12 adults out of the total 52 adults investigated) over a 3-week treatment period. Due to the erratic nature of the blood levels observed, no correlation could be made between amount of cream, degree of BSA involvement, and blood concentrations. In general, the blood concentrations measured in adult atopic dermatitis patients were comparable to those seen in the pediatric population.

In a second group of 30 pediatric patients aged 3-23 months with 10%-92% BSA involvement, following twice daily application for three weeks, blood concentrations of pimecrolimus were <2.6 ng/mL with 65% (75/116) of the blood samples having blood concentration below 0.5ng/mL, and 27% (31/116) below the limit of quantification (0.1 ng/mL) for these studies.

Overall, a higher proportion of detectable blood levels was seen in the pediatric patient population as compared to adult population. This increase in the absolute number of positive blood levels may be due to the larger surface area to body mass ratio seen in these younger subjects. In addition, a higher incidence of upper respiratory symptoms/infections was also seen relative to the older age group in the PK studies. At this time, a causal relationship between these findings and Elidel use cannot be ruled out.

Elidel Cream is not indicated for use in children less than 2 years of age (see INDICATIONS AND USAGE, WARNINGS, boxed WARNING, and PRECAUTIONS, Pediatric Use).

Renal Insufficiency

The effect of renal insufficiency on the pharmacokinetics of topically administered pimecrolimus has not been evaluated but dose-adjustment is not expected to be needed as 80% of the drug is excreted in the feces.

Hepatic Insufficiency

The effect of hepatic insufficiency on the pharmacokinetics of topically administered pimecrolimus has not been evaluated but dose-adjustment is not expected to be needed.

Clinical Studies

Three randomized, double-blind, vehicle-controlled, multicenter, Phase 3 studies were conducted in 589 pediatric patients ages 3 months-17 years old to evaluate Elidel® (pimecrolimus) Cream 1% for the treatment of mild to moderate atopic dermatitis. Two of the three trials support the use of Elidel Cream in patients 2 years and older with mild to moderate atopic dermatitis (see PRECAUTIONS, Pediatric Use). Three other trials in 1,619 pediatric and adult patients provided additional data regarding the safety of Elidel Cream in the treatment of atopic dermatitis. Two of these other trials were vehicle-controlled with optional sequential use of a medium potency topical corticosteroid in pediatric patients and one trial was an active comparator trial in adult patients with atopic dermatitis (see PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS).

Two identical 6-week, randomized, vehicle-controlled, multi-center, Phase 3 trials were conducted to evaluate Elidel Cream for the treatment of mild to moderate atopic dermatitis. A total of 403 pediatric patients 2-17 years old were included in the studies. The male/female ratio was approximately 50% and 29% of the patients were African American. At study entry, 59% of patients had moderate disease and the mean body surface area (BSA) affected was 26%. About 75% of patients had atopic dermatitis affecting the face and/or neck region. In these studies, patients applied either Elidel Cream or vehicle cream twice daily to 5% to 96% of their BSA for up to 6 weeks. At endpoint, based on the physician's global evaluation of clinical response, 35% of patients treated with Elidel Cream were clear or almost clear of signs of atopic dermatitis compared to only 18% of vehicle-treated patients. More Elidel patients (57%) had mild or no pruritus at 6 weeks compared to vehicle patients (34%). The improvement in pruritus occurred in conjunction with the improvement of the patients' atopic dermatitis.

In these two 6-week studies of Elidel, the combined efficacy results at endpoint are as follows:

	% Patients
	Elidel® (N= 267)	Vehicle (N= 136)
Global Assessment
Clear	28 (10%)	5 (4%)
Clear or Almost Clear	93 (35%)	25 (18%)
Clear to Mild Disease	180 (67%)	55 (40%)

In the two pediatric studies that independently support the use of Elidel Cream in mild to moderate atopic dermatitis, a significant treatment effect was seen by day 15. Of the key signs of atopic dermatitis, erythema, infiltration/papulation, lichenification, and excoriations, erythema and infiltration/papulation were reduced at day 8 when compared to vehicle.

The following graph depicts the time course of improvement in the percent body surface area affected as a result of treatment with Elidel Cream in 2-17 year olds.

Figure 1

The following graph shows the time course of improvement in erythema as a result of treatment with Elidel Cream in 2-17 year olds.

Figure 2

Indications and Usage for Elidel

Elidel® (pimecrolimus) Cream 1% is indicated as second-line therapy for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised adults and children 2 years of age and older, who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable.

Elidel Cream is not indicated for use in children less than 2 years of age (see WARNINGS, boxed WARNING, and PRECAUTIONS, Pediatric Use).

Contraindications

Elidel® (pimecrolimus) Cream 1% is contraindicated in individuals with a history of hypersensitivity to pimecrolimus or any of the components of the cream.

Warnings

WARNING

Long-term Safety of Topical Calcineurin Inhibitors Has Not Been Established

Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported in patients treated with topical calcineurin inhibitors, including Elidel Cream.

Therefore:

• Continuous long-term use of topical calcineurin inhibitors, including Elidel Cream, in any age group should be avoided, and application limited to areas of involvement with atopic dermatitis.


• Elidel Cream is not indicated for use in children less than 2 years of age.

Prolonged systemic use of calcineurin inhibitors for sustained immunosuppression in animal studies and transplant patients following systemic administration has been associated with an increased risk of infections, lymphomas, and skin malignancies. These risks are associated with the intensity and duration of immunosuppression.

Based on this information and the mechanism of action, there is a concern about a potential risk with the use of topical calcineurin inhibitors, including Elidel Cream. While a causal relationship has not been established, rare cases of skin malignancy and lymphoma have been reported in patients treated with topical calcineurin inhibitors, including Elidel Cream. Therefore:

• Elidel Cream should not be used in immunocompromised adults and children.


• If signs and symptoms of atopic dermatitis do not improve within 6 weeks, patients should be re-examined by their healthcare provider and their diagnosis be confirmed (see PRECAUTIONS).


• The safety of Elidel Cream has not been established beyond one year of non-continuous use.

(See CLINICAL PHARMACOLOGY, WARNINGS, boxed WARNING, PRECAUTIONS, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION.)

Precautions

General

The use of Elidel Cream should be avoided on malignant or pre-malignant skin conditions. Malignant or pre-malignant skin conditions, such as cutaneous T-cell lymphoma (CTCL), can present as dermatitis.

Elidel Cream should not be used in patients with Netherton's Syndrome or other skin diseases where there is the potential for increased systemic absorption of pimecrolimus . The safety of Elidel Cream has not been established in patients with generalized erythroderma.

The use of Elidel Cream may cause local symptoms such as skin burning (burning sensation, stinging, soreness) or pruritus. Localized symptoms are most common during the first few days of Elidel Cream application and typically improve as the lesions of atopic dermatitis resolve (see ADVERSE REACTIONS).

Bacterial and Viral Skin Infections

Before commencing treatment with Elidel Cream, bacterial or viral infections at treatment sites should be resolved. Studies have not evaluated the safety and efficacy of Elidel Cream in the treatment of clinically infected atopic dermatitis.

While patients with atopic dermatitis are predisposed to superficial skin infections including eczema herpeticum (Kaposi's varicelliform eruption), treatment with Elidel Cream may be independently associated with an increased risk of varicella zoster virus infection (chicken pox or shingles), herpes simplex virus infection, or eczema herpeticum.

In clinical studies, 15/1,544 (1%) cases of skin papilloma (warts) were observed in patients using Elidel Cream. The youngest patient was age 2 and the oldest was age 12. In cases where there is worsening of skin papillomas or they do not respond to conventional therapy, discontinuation of Elidel Cream should be considered until complete resolution of the warts is achieved.

Patients with Lymphadenopathy

In clinical studies, 14/1,544 (0.9%) cases of lymphadenopathy were reported while using Elidel Cream. These cases of lymphadenopathy were usually related to infections and noted to resolve upon appropriate antibiotic therapy. Of these 14 cases, the majority had either a clear etiology or were known to resolve. Patients who receive Elidel Cream and who develop lymphadenopathy should have the etiology of their lymphadenopathy investigated. In the absence of a clear etiology for the lymphadenopathy, or in the presence of acute infectious mononucleosis, Elidel Cream should be discontinued. Patients who develop lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.

Sun Exposure

During the course of treatment, it is prudent for patients to minimize or avoid natural or artificial sunlight exposure, even while Elidel is not on the skin. The potential effects of Elidel Cream on skin response to ultraviolet damage are not known.

Immunocompromised Patients

The safety and efficacy of Elidel Cream in immunocompromised patients have not been studied.

Information for Patients

(See Medication Guide.)

Patients using Elidel Cream should receive the following information and instructions:

What is the most important information a patient should know about Elidel Cream?

The safety of using Elidel Cream for a long period of time is not known. A very small number of people who have used Elidel Cream have had cancer (for example, skin or lymphoma). However, a link with Elidel Cream use has not been shown. Because of this concern:

• A patient should not use Elidel Cream continuously for a long time.


• Elidel Cream should be used only on areas of skin that have eczema.


• Elidel Cream is not for use on a child under 2 years old.

How should a patient use Elidel Cream?

• A patient should use Elidel Cream exactly as prescribed.


• A patient should use Elidel Cream only on areas of skin that have eczema.


• A patient should use Elidel Cream for short periods, and if needed, treatment may be repeated with breaks in between.


• A patient should stop Elidel Cream when the signs and symptoms of eczema, such as itching, rash, and redness go away, or as directed by the physician.


• A patient should follow the physician's advice if symptoms of eczema return after a treatment with Elidel Cream.


• A patient should contact the physician if:


• symptoms get worse with Elidel Cream


• the patient gets a skin infection


• if burning on the skin is severe or lasts for more than one week


• if eye irritation does not go away


• symptoms do not improve after 6 weeks of treatment

To apply Elidel Cream:

• A patient or caregiver should wash their hands before using Elidel Cream. When applying Elidel Cream after a bath or shower, the skin should be dry.


• A patient or caregiver should apply a thin layer of Elidel Cream only to the affected skin areas, twice a day, as directed by the physician.


• A patient or caregiver should use the smallest amount of Elidel Cream needed to control the signs and symptoms of eczema.


• Caregivers applying Elidel Cream to a patient, or a patient who is not treating the hands should wash their hands with soap and water after applying Elidel Cream. This should remove any cream left on the hands.


• A patient should not bathe, shower or swim right after applying Elidel Cream. This could wash off the cream.


• A patient can use moisturizers with Elidel Cream. They should be sure to check with the physician first about the products that are right for them. Because the skin of patients with eczema can be very dry, it is important they keep up good skin care practices. If a patient uses moisturizers, he or she should apply them after Elidel Cream.

What should a patient avoid while using Elidel Cream?

• A patient should not use sun lamps, tanning beds, or get treatment with ultraviolet light therapy during treatment with Elidel Cream.


• A patient should limit sun exposure during treatment with Elidel Cream even when the medicine is not on the skin. If a patient needs to be outdoors after applying Elidel Cream, the patient should wear loose fitting clothing that protects the treated area from the sun. The physician should advise the patient about other types of protection from the sun.


• A patient should not cover the skin being treated with bandages, dressings or wraps. A patient can wear normal clothing.


• Elidel Cream is for use on the skin only. Do not get Elidel Cream in your eyes, nose, mouth, vagina, or rectum (mucous membranes). If you get Elidel Cream in any of these areas, burning or irritation can happen. Wipe off any Elidel Cream from the affected area and then rinse the area well with cold water. Elidel Cream is for external use only.


• A patient should not swallow Elidel Cream and should contact the physician if they do.

Drug Interactions

Potential interactions between Elidel and other drugs, including immunizations, have not been systematically evaluated. Due to low blood levels of pimecrolimus detected in some patients after topical application, systemic drug interactions are not expected, but cannot be ruled out. The concomitant administration of known CYP3A family of inhibitors in patients with widespread and/or erythrodermic disease should be done with caution. Some examples of such drugs are erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers and cimetidine.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year rat dermal carcinogenicity study using Elidel Cream, a statistically significant increase in the incidence of follicular cell adenoma of the thyroid was noted in low, mid and high dose male animals compared to vehicle and saline control male animals. Follicular cell adenoma of the thyroid was noted in the dermal rat carcinogenicity study at the lowest dose of 2 mg/kg/day [0.2% pimecrolimus cream; 1.5× the Maximum Recommended Human Dose (MRHD) based on AUC comparisons]. No increase in the incidence of follicular cell adenoma of the thyroid was noted in the oral carcinogenicity study in male rats up to 10 mg/kg/day (66× MRHD based on AUC comparisons). However, oral studies may not reflect continuous exposure or the same metabolic profile as by the dermal route. In a mouse dermal carcinogenicity study using pimecrolimus in an ethanolic solution, no increase in incidence of neoplasms was observed in the skin or other organs up to the highest dose of 4 mg/kg/day (0.32% pimecrolimus in ethanol) 27× MRHD based on AUC comparisons. However, lymphoproliferative changes (including lymphoma) were noted in a 13 week repeat dose dermal toxicity study conducted in mice using pimecrolimus in an ethanolic solution at a dose of 25 mg/kg/day (47× MRHD based on AUC comparisons). No lymphoproliferative changes were noted in this study at a dose of 10 mg/kg/day (17× MRHD based on AUC comparison). However, the latency time to lymphoma formation was shortened to 8 weeks after dermal administration of pimecrolimus dissolved in ethanol at a dose of 100 mg/kg/day (179-217× MRHD based on AUC comparisons).

In a mouse oral (gavage) carcinogenicity study, a statistically significant increase in the incidence of lymphoma was noted in high dose male and female animals compared to vehicle control male and female animals. Lymphomas were noted in the oral mouse carcinogenicity study at a dose of 45 mg/kg/day (258-340× MRHD based on AUC comparisons). No drug-related tumors were noted in the mouse oral carcinogenicity study at a dose of 15 mg/kg/day (60-133× MRHD based on AUC comparisons). In an oral (gavage) rat carcinogenicity study, a statistically significant increase in the incidence of benign thymoma was noted in 10 mg/kg/day pimecrolimus treated male and female animals compared to vehicle control treated male and female animals. In addition, a significant increase in the incidence of benign thymoma was noted in another oral (gavage) rat carcinogenicity study in 5 mg/kg/day pimecrolimus treated male animals compared to vehicle control treated male animals. No drug-related tumors were noted in the rat oral carcinogenicity study at a dose of 1 mg/kg/day male animals (1.1× MRHD based on AUC comparisons) and at a dose of 5 mg/kg/day for female animals (21× MRHD based on AUC comparisons).

In a 52-week dermal photo-carcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing with concurrent exposure to UV radiation (40 weeks of treatment followed by 12 weeks of observation) with the Elidel Cream vehicle alone. No additional effect on tumor development beyond the vehicle effect was noted with the addition of the active ingredient, pimecrolimus, to the vehicle cream.

A 39-week oral monkey toxicology study was conducted with pimecrolimus doses of 15, 45 and 120 mg/kg/day. A dose dependent increase in expression of immunosuppressive-related lymphoproliferative disorder (IRLD) associated with lymphocryptovirus (a monkey strain of virus related to human Epstein Barr virus) was observed. IRLD in monkeys mirrors what has been noted in human transplant patients after chronic systemic immunosuppressive therapy, post transplantation lymphoproliferative disease (PTLD), after treatment with chronic systemic immunosuppressive therapy. Both IRLD and PTLD can progress to lymphoma, which is dependent on the dose and duration of systemic immunosuppressive therapy. A dose dependent increase in opportunistic infections (a signal of systemic immunosuppression) was also noted in this monkey study. A no observed adverse effect level (NOAEL) for IRLD and opportunistic infections was not established in this study. IRLD occurred at the lowest dose of 15 mg/kg/day for 39 weeks [31× the Maximum Recommended Human Dose (MRHD) of Elidel Cream based on AUC comparisons] in this study. A partial recovery from IRLD was noted upon cessation of dosing in this study.

A battery of in vitro genotoxicity tests, including Ames assay, mouse lymphoma L5178Y assay, and chromosome aberration test in V79 Chinese hamster cells and an in vivo mouse micronucleus test revealed no evidence for a mutagenic or clastogenic potential for the drug.

An oral fertility and embryofetal developmental study in rats revealed estrus cycle disturbances, post-implantation loss and reduction in litter size at the 45 mg/kg/day dose (38× MRHD based on AUC comparisons). No effect on fertility in female rats was noted at 10 mg/kg/day (12× MRHD based on AUC comparisons). No effect on fertility in male rats was noted at 45 mg/kg/day (23× MRHD based on AUC comparisons), which was the highest dose tested in this study.

A second oral fertility and embryofetal developmental study in rats revealed reduced testicular and epididymal weights, reduced testicular sperm counts and motile sperm for males and estrus cycle disturbances, decreased corpora lutea, decreased implantations and viable fetuses for females at 45 mg/kg/day dose (123× MRHD for males and 192× MRHD for females based on AUC comparisons). No effect on fertility in female rats was noted at 10 mg/kg/day (5× MRHD based on AUC comparisons). No effect on fertility in male rats was noted at 2 mg/kg/day (0.7× MRHD based on AUC comparisons).

Pregnancy

Teratogenic Effects

Pregnancy Category C

There are no adequate and well-controlled studies of topically administered pimecrolimus in pregnant women. The experience with Elidel Cream when used by pregnant women is too limited to permit assessment of the safety of its use during pregnancy.

In dermal embryofetal developmental studies, no maternal or fetal toxicity was observed up to the highest practicable doses tested, 10 mg/kg/day (1% pimecrolimus cream) in rats (0.14× MRHD based on body surface area) and 10 mg/kg/day (1% pimecrolimus cream) in rabbits (0.65× MRHD based on AUC comparisons). The 1% pimecrolimus cream was administered topically for 6 hours/day during the period of organogenesis in rats and rabbits (gestational days 6-21 in rats and gestational days 6-20 in rabbits).

A second dermal embryofetal development study was conducted in rats using pimecrolimus cream applied dermally to pregnant rats (1 g cream/kg body weight of 0.2%, 0.6% and 1.0% pimecrolimus cream) from gestation day 6 to 17 at doses of 2, 6, and 10 mg/kg/day with daily exposure of approximately 22 hours. No maternal, reproductive, or embryo-fetal toxicity attributable to pimecrolimus was noted at 10 mg/kg/day (0.66× MRHD based on AUC comparisons), the highest dose evaluated in this study. No teratogenicity was noted in this study at any dose.

A combined oral fertility and embryofetal developmental study was conducted in rats and an oral embryofetal developmental study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis (2 weeks prior to mating until gestational day 16 in rats, gestational days 6-18 in rabbits) up to dose levels of 45 mg/kg/day in rats and 20 mg/kg/day in rabbits. In the absence of maternal toxicity, indicators of embryofetal toxicity (post-implantation loss and reduction in litter size) were noted at 45 mg/kg/day (38× MRHD based on AUC comparisons) in the oral fertility and embryofetal developmental study conducted in rats. No malformations in the fetuses were noted at 45 mg/kg/day (38× MRHD based on AUC comparisons) in this study. No maternal toxicity, embryotoxicity or teratogenicity were noted in the oral rabbit embryofetal developmental toxicity study at 20 mg/kg/day (3.9× MRHD based on AUC comparisons), which was the highest dose tested in this study.

A second oral embryofetal development study was conducted in rats. Pimecrolimus was administered during the period of organogenesis (gestational days 6 – 17) at doses of 2, 10 and 45 mg/kg/day. Maternal toxicity, embryolethality and fetotoxicity were noted at 45 mg/kg/day (271× MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, embryolethality or fetotoxicity were noted at 10 mg/kg/day (16× MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose.

A second oral embryofetal development study was conducted in rabbits. Pimecrolimus was administered during the period of organogenesis (gestational days 7 – 20) at doses of 2, 6 and 20 mg/kg/day. Maternal toxicity, embryotoxicity and fetotoxicity were noted at 20 mg/kg/day (12× MRHD based on AUC comparisons). A slight increase in skeletal variations that were indicative of delayed skeletal ossification was also noted at this dose. No maternal toxicity, embryotoxicity or fetotoxicity were noted at 6 mg/kg/ day (5× MRHD based on AUC comparisons). No teratogenicity was noted in this study at any dose.

An oral peri- and post-natal developmental study was conducted in rats. Pimecrolimus was administered from gestational day 6 through lactational day 21 up to a dose level of 40 mg/kg/day. Only 2 of 22 females delivered live pups at the highest dose of 40 mg/kg/day. Postnatal survival, development of the F1 generation, their subsequent maturation and fertility were not affected at 10 mg/kg/day (12× MRHD based on AUC comparisons), the highest dose evaluated in this study.

Pimecrolimus was transferred across the placenta in oral rat and rabbit embryofetal developmental studies.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used only if clearly needed during pregnancy.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pimecrolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Elidel Cream is not indicated for use in children less than 2 years of age.

The long-term safety and effects of Elidel Cream on the developing immune system are unknown (see WARNINGS, boxed WARNING, and INDICATIONS AND USAGE).

Three Phase 3 pediatric studies were conducted involving 1,114 patients 2-17 years of age. Two studies were 6-week randomized vehicle-controlled studies with a 20-week open-label phase and one was a vehicle-controlled (up to 1 year) safety study with the option for sequential topical corticosteroid use. Of these patients 542 (49%) were 2-6 years of age. In the short-term studies, 11% of Elidel patients did not complete these studies and 1.5% of Elidel patients discontinued due to adverse events. In the one-year study, 32% of Elidel patients did not complete this study and 3% of Elidel patients discontinued due to adverse events. Most discontinuations were due to unsatisfactory therapeutic effect.

The most common local adverse event in the short-term studies of Elidel Cream in pediatric patients ages 2-17 was application site burning (10% vs. 13% vehicle); the incidence in the long-term study was 9% Elidel vs. 7% vehicle (see ADVERSE REACTIONS). Adverse events that were more frequent (>5%) in patients treated with Elidel Cream compared to vehicle were headache (14% vs. 9%) in the short-term trial. Nasopharyngitis (26% vs. 21%), influenza (13% vs. 4%), pharyngitis (8% vs. 3%), viral infection (7% vs. 1%), pyrexia (13% vs. 5%), cough (16% vs. 11%), and headache (25% vs. 16%) were increased over vehicle in the 1-year safety study (see ADVERSE REACTIONS). In 843 patients ages 2-17 years treated with Elidel Cream, 9 (0.8%) developed eczema herpeticum (5 on Elidel Cream alone and 4 on Elidel Cream used in sequence with corticosteroids). In 211 patients on vehicle alone, there were no cases of eczema herpeticum. The majority of adverse events were mild to moderate in severity.

Two Phase 3 studies were conducted involving 436 infants age 3 months-23 months. One 6-week randomized vehicle-controlled study with a 20-week open-label phase and one safety study, up to one year, were conducted. In the 6-week study, 11% of Elidel and 48% of vehicle patients did not complete this study; no patient in either group discontinued due to adverse events. Infants on Elidel Cream had an increased incidence of some adverse events compared to vehicle. In the 6-week vehicle-controlled study these adverse events included pyrexia (32% vs. 13% vehicle), URI (24% vs. 14%), nasopharyngitis (15% vs. 8%), gastroenteritis (7% vs. 3%), otitis media (4% vs. 0%), and diarrhea (8% vs. 0%). In the open-label phase of the study, for infants who switched to Elidel Cream from vehicle, the incidence of the above-cited adverse events approached or equaled the incidence of those patients who remained on Elidel Cream. In the 6 month safety data, 16% of Elidel and 35% of vehicle patients discontinued early and 1.5% of Elidel and 0% of vehicle patients discontinued due to adverse events. Infants on Elidel Cream had a greater incidence of some adverse events as compared to vehicle. These included pyrexia (30% vs. 20%), URI (21% vs. 17%), cough (15% vs. 9%), hypersensitivity (8% vs. 2%), teething (27% vs. 22%), vomiting (9% vs. 4%), rhinitis (13% vs. 9%), viral rash (4% vs. 0%), rhinorrhea (4% vs. 0%), and wheezing (4% vs. 0%).

Geriatric Use

Nine (9) patients ≥65 years old received Elidel Cream in Phase 3 studies. Clinical studies of Elidel did not include sufficient numbers of patients aged 65 and over to assess efficacy and safety.

Adverse Reactions

No phototoxicity and no photoallergenicity were detected in clinical studies with 24 and 33 normal volunteers, respectively. In human dermal safety studies, Elidel® (pimecrolimus) Cream 1% did not induce contact sensitization or cumulative irritation.

In a one-year safety study in pediatric patients age 2-17 years old involving sequential use of Elidel Cream and a topical corticosteroid, 43% of Elidel patients and 68% of vehicle patients used corticosteroids during the study. Corticosteroids were used for more than 7 days by 34% of Elidel patients and 54% of vehicle patients. An increased incidence of impetigo, skin infection, superinfection (infected atopic dermatitis), rhinitis, and urticaria were found in the patients that had used Elidel Cream and topical corticosteroid sequentially as compared to Elidel Cream alone.

In 3 randomized, double-blind vehicle-controlled pediatric studies and one active-controlled adult study, 843 and 328 patients respectively, were treated with Elidel Cream. In these clinical trials, 48 (4%) of the 1,171 Elidel patients and 13 (3%) of 408 vehicle-treated patients discontinued therapy due to adverse events. Discontinuations for AEs were primarily due to application site reactions, and cutaneous infections. The most common application site reaction was application site burning, which occurred in 8%-26% of patients treated with Elidel Cream.

The following table depicts the incidence of adverse events pooled across the 2 identically designed 6-week studies with their open label extensions and the 1-year safety study for pediatric patients ages 2-17. Data from the adult active-controlled study is also included in this table. Adverse events are listed regardless of relationship to study drug.

Two cases of septic arthritis have been reported in infants less than one year of age in clinical trials conducted with Elidel Cream (n = 2,443). Causality has not been established.

POST-MARKETING EVENTS

The following adverse reactions have been reported in patients using Elidel Cream. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General

Anaphylactic reactions, ocular irritation after application of the cream to the eye lids or near the eyes, angioneurotic edema, facial edema, skin flushing associated with alcohol use, skin discoloration

Hematology/Oncology

Lymphomas, basal cell carcinoma, malignant melanoma, squamous cell carcinoma

Overdosage

There has been no experience of overdose with Elidel® (pimecrolimus) Cream 1%. If oral ingestion occurs, medical advice should be sought.

Elidel Dosage and Administration

• The patient or care giver should apply a thin layer of Elidel (pimecrolimus) Cream 1% to the affected skin twice daily. The patient or caregiver should stop using when signs and symptoms (e.g., itch, rash and redness) resolve and should be instructed on what actions to take if symptoms recur.


• If signs and symptoms persist beyond 6 weeks, patients should be re-examined by their health care provider to confirm the diagnosis of atopic dermatitis.


• Continuous long-term use of Elidel Cream should be avoided, and application should be limited to areas of involvement with atopic dermatitis.

The safety of Elidel Cream under occlusion, which may promote systemic exposure, has not been evaluated. Elidel Cream should not be used with occlusive dressings.

How is Elidel Supplied

Elidel® (pimecrolimus) Cream 1% is available in tubes of 30 grams, 60 grams, and 100 grams.

30 gram tube	NDC 0187-5100-01
60 gram tube	NDC 0187-5101-02
100 gram tube	NDC 0187-5102-03

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Do not freeze.

Treatment Emergent Adverse Events ( ≥1%) in Elidel® Treatment Groups

	Pediatric Patients* Vehicle-Controlled		Pediatric Patients* Open-Label	Pediatric Patients* Vehicle-Controlled		Adult Active Comparator
	(6 weeks)		(20 weeks)	(1 year)		(1 year)
	Elidel® Cream	Vehicle	Elidel® Cream	Elidel® Cream	Vehicle	Elidel® Cream
	(N=267) N (%)	(N=136) N (%)	(N=335) N (%)	(N=272) N (%)	(N=75) N (%)	(N=328) N (%)
* Ages 2-17 years
At least 1 AE	182 (68.2%)	97 (71.3%)	240 (72.0%)	230 (84.6%)	56 (74.7%)	256 (78.0%)
Infections and Infestations
Upper Respiratory Tract Infection NOS	38 (14.2%)	18 (13.2%)	65 (19.4%)	13 (4.8%)	6 (8.0%)	14 (4.3%)
Nasopharyngitis	27 (10.1%)	10 (7.4%)	32 (19.6%)	72 (26.5%)	16 (21.3%)	25 (7.6%)
Skin Infection NOS	8 (3.0%)	9 (5.1%)	18 (5.4%)	6 (2.2%)	3 (4.0%)	21 (6.4%)
Influenza	8 (3.0%)	1 (0.7%)	22 (6.6%)	36 (13.2%)	3 (4.0%)	32 (9.8%)
Ear Infection NOS	6 (2.2%)	2 (1.5%)	19 (5.7%)	9 (3.3%)	1 (1.3%)	2 (0.6%)
Otitis Media	6 (2.2%)	1 (0.7%)	10 (3.0%)	8 (2.9%)	4 (5.3%)	2 (0.6%)
Impetigo	5 (1.9%)	3 (2.2%)	12 (3.6%)	11 (4.0%)	4 (5.3%)	8 (2.4%)
Bacterial Infection	4 (1.5%)	3 (2.2%)	4 (1.2%)	3 (1.1%)	0	6 (1.8%)
Folliculitis	3 (1.1%)	1 (0.7%)	3 (0.9%)	6 (2.2%)	3 (4.0%)	20 (6.1%)
Sinusitis	3 (1.1%)	1 (0.7%)	11 (3.3%)	6 (2.2%)	1 (1.3%)	2 (0.6%)
Pneumonia NOS	3 (1.1%)	1 (0.7%)	5 (1.5%)	0	1 (1.3%)	1 (0.3%)
Pharyngitis NOS	2 (0.7%)	2 (1.5%)	3 (0.9%)	22 (8.1%)	2 (2.7%)	3 (0.9%)
Pharyngitis Streptococcal	2 (0.7%)	2 (1.5%)	10 (3.0%)	0	<1%	0
Molluscum Contagiosum	2 (0.7%)	0	4 (1.2%)	5 (1.8%)	0	0
Staphylococcal Infection	1 (0.4%)	5 (3.7%)	7 (2.1%)	0	<1%	3 (0.9%)
Bronchitis NOS	1 (0.4%)	3 (2.2%)	4 (1.2%)	29 (10.7%)	6 (8.0%)	8 (2.4%)
Herpes Simplex	1 (0.4%)	0	4 (1.2%)	9 (3.3%)	2 (2.7%)	13 (4.0%)
Tonsillitis NOS	1 (0.4%)	0	3 (0.9%)	17 (6.3%)	0

Advicor

Generic Name: lovastatin and niacin (Oral route)

NYE-a-sin, loe-va-STAT-in

Commonly used brand name(s)

In the U.S.

• Advicor

Available Dosage Forms:

• Tablet


• Tablet, Extended Release

Therapeutic Class: Antihyperlipidemic

Pharmacologic Class: Vitamin B

Chemical Class: Nicotinic Acid (class)

Uses For Advicor

Niacin extended-release and Lovastatin combination medicine is used to help lower high cholesterol and fat levels in the blood. This may help prevent medical problems caused by cholesterol and fat clogging the blood vessels.

Niacin extended-release and lovastatin combination medicine combines two drugs that work together to treat cholesterol and lipid (fat) disorders. Niacin is a B-complex vitamin that reduces the amount of cholesterol in the blood. Lovastatin belongs to the group of medicines called 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. It works by blocking an enzyme that is needed by the body to make cholesterol, thereby reducing the amount of cholesterol in the blood

This medicine is available only with your doctor's prescription.

Before Using Advicor

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:

This combination medicine should not be used until after your body has adjusted to each of the individual medicines. Be sure to check with your doctor about this.

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

Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of niacin extended-release and lovastatin combination in children with use in other age groups.

Geriatric

This medicine has been tested in a limited number of patients 65 years of age or older and has not been shown to cause different side effects or problems in older people than it does in younger adults.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	X	Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while 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. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Atazanavir


• Boceprevir


• Clarithromycin


• Darunavir


• Fosamprenavir


• Itraconazole


• Lopinavir


• Mibefradil


• Ritonavir


• Saquinavir


• Telaprevir


• Tipranavir

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amiodarone


• Amprenavir


• Atorvastatin


• Bezafibrate


• Cerivastatin


• Ciprofibrate


• Clofibrate


• Colchicine


• Conivaptan


• Cyclosporine


• Dalfopristin


• Danazol


• Daptomycin


• Delavirdine


• Erythromycin


• Everolimus


• Fenofibrate


• Fluconazole


• Gemfibrozil


• Indinavir


• Ketoconazole


• Lovastatin


• Nefazodone


• Nelfinavir


• Niacin


• Pitavastatin


• Posaconazole


• Quinupristin


• Ranolazine


• Rosuvastatin


• Simvastatin


• Telithromycin


• Verapamil

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Azithromycin


• Bosentan


• Diltiazem


• Oat Bran


• Pectin


• St John's Wort


• Voriconazole


• Warfarin

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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol


• Grapefruit Juice

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:

• Bleeding problems or


• Diabetes mellitus (sugar diabetes) or


• Endocrine problems or


• Gout or


• Heart Disease or


• Liver disease or


• Low blood pressure or


• Stomach Ulcer—Niacin extended-release and lovastatin combination may make these conditions worse.

• Kidney Disease—Effects of niacin extended-release and lovastatin combination may be increased because of slower removal of medicine from the body.

Proper Use of Advicor

Before prescribing medicine for your condition, your doctor will probably try to control your condition by prescribing a personal diet for you. Such a diet may be low in fats, particularly saturated fat, sugars, and/or cholesterol. Many people are able to control their condition by carefully following their doctor's orders for proper diet and exercise. Medicine is prescribed only when additional help is needed and is effective only when a schedule of diet and exercise is properly followed.

Make certain your doctor knows if you are on any special diet, such as a low-sodium or low-sugar diet.

Use this medicine only as directed by your doctor. Do not use more or less of it, and do not use it more often or for a longer time than your doctor ordered. Also, this medicine works best if there is a constant amount in the blood. To help keep this amount constant, do not miss any doses and take the medicine at the same time each day.

Remember that this medicine will not cure your condition but it does help control it. Therefore, you must continue to take it as directed to keep your cholesterol levels down.

Follow carefully the special diet your doctor gave you.This is an important part of controlling your condition, and is necessary if the medicine is to work properly.

Do not drink any grapefruit juice around the time you take this medicine. It may be best to drink any grapefruit juice approximately 12 hours before or after you take your medicine. In addition, do not drink grapefruit juice in large quantities (more than one quart per day) while you are being treated with niacin extended-release and lovastatin combination. To do so may increase the risk of developing muscle problems. Check with your doctor if you have any questions.

Take this medicine at bedtime after eating a low fat snack. Swallow the tablet whole. Do not crush, break, or chew the tablet before you swallow it.

This medicine may cause you to have skin flushing which makes your face, neck, arms and occasionally, your upper chest to feel warm and look red. Flushing usually starts about two to four hours after you take your medicine, and may last up to several hours. Flushing can also cause itching and/or a tingling sensation. A more intense episode of flushing may include dizziness or faintness. If you take your medicine at bedtime, you may sleep through any flushing that occurs. If awakened by flushing, rise slowly to minimize the potential for dizziness or fainting. Avoiding alcohol or hot drinks may reduce the flushing. This effect should lessen after several weeks as your body gets used to the medicine. However, if the problem continues or gets worse, 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 oral dosage form (tablets):
  
  • 
    
    • Adults—The starting dose is usually, 500 milligrams (mg) of niacin extended-release and 20 mg of lovastatin (combined in one tablet) one time a day, at bedtime with a low fat snack. Then your doctor may increase your dose a little at a time every 4 weeks, as your body gets used to the medicine, until your cholesterol is controlled.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take 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. Do not double doses.

If you have not taken this medicine for more than 7 days, check with your doctor. You may need to have your dose reduced before you can start taking this medicine again.

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 Advicor

Check with your doctor immediately if you have dark-colored urine, a fever, muscle cramps or spasms, muscle pain or stiffness, or feel very tired or weak.Niacin extended-release and lovastatin combination may cause a serious, but rare, problem called rhabdomyolysis. It is important to call your doctor right away if you have any of these symptoms.

It is very important that your doctor check your progress at regular visits.This will allow your doctor to see if the medicine is working properly to lower your cholesterol and triglyceride (fat) levels and that it does not cause unwanted side effects. At regular intervals, your doctor will want to do routine blood tests.

For diabetic patients: This medicine may affect blood sugar levels. If you notice a change in the results of your blood or urine sugar tests or if you have any questions, check with your doctor.

Do not stop taking niacin extended-release and lovastatin combination without first checking with your doctor. When you stop taking this medicine, your blood cholesterol levels may increase again.

Check with your doctor immediately if you think that you may be pregnant. Niacin extended-release and lovastatin combination may cause birth defects or other problems in the baby if taken during pregnancy.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine.

Advicor 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:

More common

• Asthenia, such as, lack or loss of strength


• infection, such as, cough or hoarseness, fever or chills, lower back or side pain, painful or difficult urination


• pain

Less common

• Abdominal pain, such as, stomach pain


• hyperglycemia, such as, abdominal pain, blurred vision, dry mouth, fatigue, dry skin, fruit-like breath odor, increased hunger, increased thirst, increased urination, nausea, unexplained weight loss, vomiting


• myalgia, such as, difficulty in moving, joint pain, muscle aching, cramping pain or stiffness, swollen joints


• myopathy, such as, muscle aches, weakness, tenderness, or pain


• stomach pain

Rare

• Rhabdomyolysis, such as, dark-colored urine, fever, muscle cramps, pain, spasm, or stiffness, unusual tiredness or weakness

Symptoms of Overdose

Get emergency help immediately if any of the following symptoms of overdose occur:

• Cardiac arrhythmia, such as, chest pain or discomfort, dizziness, fainting, fast, slow or irregular heartbeat, lightheadedness, pounding or rapid pulse


• diarrhea


• dizziness


• flushing, severe, such as, feeling of warmth, redness, itching, and/or tingling of the face, neck, arms, and occasionally, upper chest, dizziness, fainting


• hypotension, such as, blurred vision, confusion, dizziness, faintness, lightheadedness when getting up from a lying or sitting position, sudden sweating, unusual tiredness or weakness


• nausea and vomiting


• syncope, such as, fainting

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

• Chills


• diarrhea


• flu syndrome, such as, chills, diarrhea, fever, general feeling of discomfort or illness, headache, joint pain, loss of appetite, muscle aches and pains, nausea, runny nose, shivering, sore throat, sweating, trouble sleeping, unusual tiredness or weakness, vomiting


• flushing, such as, feeling of warmth, redness, itching, and/or tingling of the face, neck, arms, and occasionally, upper chest


• edema, such as, swelling


• headache


• nausea


• pruritus, such as, itching skin


• rash


• shortness of breath


• sweating


• syncope, such as, feeling faint or fainting


• tachycardia, such as, fast, pounding, or irregular heartbeat or pulse

Less common

• dyspepsia, such as, acid or sour stomach, belching, heartburn, indigestion, stomach discomfort, upset or pain

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: Advicor 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 Advicor resources

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

• Advicor Prescribing Information (FDA)


• Advicor Concise Consumer Information (Cerner Multum)


• Advicor MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Advicor with other medications

• High Cholesterol
• High Cholesterol, Familial Heterozygous
• Hyperlipoproteinemia
• Hyperlipoproteinemia Type IIa, Elevated LDL
• Hyperlipoproteinemia Type IIb, Elevated LDL VLDL

Meniere's Disease Medications

Definition of Meniere's Disease: A name applied to recurrent vertigo accompanied by ringing in the ears

Drugs associated with Meniere's Disease

The following drugs and medications are in some way related to, or used in the treatment of Meniere's Disease. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

Learn more about Meniere's Disease

Medical Encyclopedia:

• Meniere's disease

Harvard Health Guide:

• Symptoms and treatment for Meniere's Disease

Drug List:

Valium

Valrelease

Vontrol

Allergenic Extract, Cotton,Jute,Kapok,Orris-Root,Pyrethrum,Tobacco Leaf

Allergenic Extract

WARNINGS

Allergenic extract is intended for use by, or under the guidance of, physicians who are experienced in the administration of allergenic extracts for diagnosis and/or immunotherapy and the emergency care of anaphylaxis. This extract is not directly interchangeable with other allergenic extracts. The initial dose must be based on skin testing as described in the “DOSAGE AND ADMINISTRATION” section of this insert. Patients switching from other types of extracts to Antigen Laboratories’ allergenic extracts should be started as if they were undergoing treatment for the first time. Patients being switched from one lot of extract to another from the same manufacturer should have the dose reduced by 75%.

Severe systemic reactions may occur with all allergenic extracts. In certain individuals, especially in steroid-dependent/unstable asthmatics, these life-threatening reactions may result in death. Patients should be observed for at least 20 minutes following allergenic extract injections. Treatment and emergency measures, as well as personnel trained in their use, must be available in the event of a life-threatening reaction. Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and/or death. Report serious adverse events to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, phone 1-800-FDA-1088.

This product should not be injected intravenously. Deep subcutaneous routes have proven to be safe. See the “WARNINGS”, “PRECAUTIONS”, “ADVERSE REACTIONS” and “OVERDOSAGE” sections.

Patients receiving beta-blockers may not be responsive to epinephrine or inhaled bronchodilators. Respiratory obstruction not responding to parenteral or inhaled bronchodilators may require theophylline, oxygen, intubation and the use of life support systems. Parenteral fluid and/or plasma expanders may be utilized for treatment of shock. Adrenocorticosteroids may be administered parenterally or intravenously. Refer to “WARNINGS”, “PRECAUTIONS” and “ADVERSE REACTIONS” sections below.

Allergenic Extract, Cotton,Jute,Kapok,Orris-Root,Pyrethrum,Tobacco Leaf Description

Antigen Laboratories’ allergenic extracts are manufactured from source material listed on the vial label. Lower concentrations (e.g. 1:50, 1:33, etc.) may be prepared either by dilution from a more concentrated stock or by direct extraction. The extract is a sterile solution containing extractables of source materials obtained from biological collecting and/or processing firms and Antigen Laboratories. All source materials are inspected by Antigen Laboratories’ technical personnel in accordance with 21 CFR 680.1 (b) (1). The route of administration for immunotherapy is subcutaneous. The routes of administration for diagnostic purposes are intradermal or prick-puncture of the skin.

FOR ALLERGENIC EXTRACTS CONTAINING 50% V/V GLYCERINE AS PRESERVATIVE AND STABILIZER:

INACTIVE INGREDIENTS:

Sodium chloride…………………………………………………………….0.95%

Sodium bicarbonate………………………………………………………..0.24%

Glycerine…………………………………………………………………50% (v/v)

Water for Injection…………………………………………………q.s. to volume

Active allergens are described by common and scientific name on the stock concentrate container label or on last page of this circular.

Food allergenic extracts may be manufactured on a weight/volume (w/v) or volume/volume (v/v) basis. Food extracts made from dried raw material are extracted at 2-10% (1:50-1:10 w/v ratio) in extracting fluid containing 50% glycerine. Slurries of juicy fruits or vegetables (prepared with a minimum amount of water for injection) are combined with an equal volume of glycerine for a ration of 1:1 volume/volume (v/v). Sodium chloride and sodium bicarbonate are added to the slurry and glycerine mixture. Fresh egg white extract is prepared by adding one part raw egg white to nine parts of extracting fluid (1:9 v/v).

Antigen E is considered the most important allergen of Short Ragweed pollen and is used for the standardization of Short Ragweed allergenic extracts. Stock mixtures containing Short Ragweed are analyzed for Antigen E content by radial immunodiffusion using Center for Biologics Evaluation and Research (CBER) references and anti-serum. Antigen E content expressed as units of Antigen E per milliliter (U/ml) is printed on container label.

Allergenic Extract, Cotton,Jute,Kapok,Orris-Root,Pyrethrum,Tobacco Leaf - Clinical Pharmacology

Studies indicate allergic individuals produce immunoglobulins of the IgE class in response to exposure to allergens. Subsequent exposure to the allergen results in a combination of allergen with IgE antibody fixed on mast cells or basophil membranes. This cross-linking results in stimulation of mast cell which leads to release and generation of pharmacologically active substances that produce immediate hypersensitivity reaction.3

The mode of action of immunotherapy with allergenic extracts is still under investigation. Subcutaneous injections of increasing doses of allergenic extract into patients with allergic disease have been shown to result in both humoral and cellular changes including the production of allergen-specific IgG antibodies, the suppression of histamine release from target cells, decrease in circulating levels of antigen specific IgE antibody over long periods of time and suppression of peripheral blood T-lymphocyte cell responses to antigen.10, 14, 15

Indications and Usage for Allergenic Extract, Cotton,Jute,Kapok,Orris-Root,Pyrethrum,Tobacco Leaf

Allergenic extract is used for diagnostic testing and for the treatment (immunotherapy) of patients whose histories indicate that upon natural exposure to the allergen, they experience allergic symptoms. Confirmation is determined by skin testing. Diagnostic use of allergenic extracts usually begins with direct skin testing. This product is not intended for treatment of patients who do not manifest immediate hypersensitivity reactions to the allergenic extract following skin testing.

Contraindications

Do not administer in the presence of diseases characterized by bleeding diathesis. Individuals with autoimmune disease may be at risk of exacerbating symptoms of the underlying disease, possibly due to routine immunization. Patients who have experienced a recent myocardial infarction may not be tolerant of immunotherapy. Children with nephrotic syndrome probably should not receive injections due to immunization causing exacerbation of nephrotic disease.

Warnings

Refer to boxed “WARNINGS”, “PRECAUTIONS”, “ADVERSE REACTIONS” and “OVERDOSAGE” sections for additional information on serious adverse reactions and steps to be taken, if any occur.

Extreme caution is necessary when using diagnostic skin tests or injection treatment in highly sensitive patients who have experienced severe symptoms or anaphylaxis by natural exposure, or during previous skin testing or treatment. IN THESE CASES THE POTENCY FOR SKIN TESTS AND THE ESCALATION OF THE TREATMENT DOSE MUST BE ADJUSTED TO THE PATIENT’S SENSITIVITY AND TOLERANCE.

Benefit versus risk needs to be evaluated in steroid dependent asthmatics, patients with unstable asthma or patients with underlying cardiovascular disease.

Injections should never be given intravenously. A 5/8 inch, 25 gauge needle on a sterile syringe allows deep subcutaneous injection. Withdraw plunger slightly after inserting needle to determine if a blood vessel has been entered.

Proper measurement of dose and caution in making injection will minimize reactions. Adverse reactions to allergenic extracts are usually apparent within 20-30 minutes following injection of immunotherapy.

Extract should be temporarily withheld or dosage reduced in case of any of the following conditions: 1) flu or other infection with fever; 2) exposure to excessive amounts of allergen prior to injection; 3) rhinitis and/or asthma exhibiting severe symptoms; 4) adverse reaction to previous injection until cause of reaction has been evaluated by physician supervising patient’s immunotherapy program.

Precautions

General:

Immunotherapy must be given under physician’s supervision. Sterile solutions, vials, syringes, etc. must be used. Aseptic technique must be observed in making dilutions from stock concentrates. The usual precautions in administering allergenic extracts are necessary, refer to boxed WARNINGS and “WARNINGS” section. Sterile syringe and needle must be used for each individual patient to prevent transmission of serum hepatitis, Human Immunodeficiency Virus (HIV) and other infectious agents.

Epinephrine 1:1000 should be available. Refer to “OVERDOSAGE” section for description of treatment for anaphylactic reactions.

Information for Patients:

Patient should remain under observation of a nurse, physician, or personnel trained in emergency measures for at least 20 minutes following immunotherapy injection. Patient must be instructed to report any adverse reactions that occur within 24 hours after injection. Possible adverse reactions include unusual swelling and/or tenderness at injection site, rhinorrhea, sneezing, coughing, wheezing, shortness of breath, nausea, dizziness, or faintness. Immediate medical attention must be sought for reactions that occur during or after leaving physician’s office.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Long term studies in animals have not been conducted with allergenic extract to determine their potential for carcinogenicity, mutagenicity or impairment of fertility.

Pregnancy Category C:

Animal reproduction studies have not been conducted with allergenic extracts. It is not known whether allergenic extracts cause fetal harm during pregnancy or affect reproductive capacity. A systemic reaction to allergenic extract could cause uterine contractions leading to spontaneous abortion or premature labor. Allergenic extracts should be used during pregnancy only if potential benefit justifies potential risk to fetus.11

Nursing Mothers:

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

Pediatric Use:

Allergenic extracts have been used routinely in children, and no special safety problems or specific hazards have been found. Children can receive the same dose as adults. Discomfort is minimized by dividing the dose in half and administering injection at two different sites.16, 17

Drug Interactions:

Antihistamines. Antihistamines inhibit the wheal and flare reaction. The inhibitory effect of conventional antihistamines varies from 1 day up to 10 days, according to the drug and patient’s sensitivity. Long acting antihistamines (e.g., astemizole) may inhibit the wheal and flare for up to forty days.1, 2

Imipramines, phenothiazines, and tranquilizers. Tricyclic antidepressants exert a potent and sustained decrease of skin reactions to histamine. This effect may last for a few weeks. Tranquilizers and antiemetic agents of the phenothiazine class have H1 antihistaminic activity and can block skin tests.1

Corticosteroids. Short-term (less than 1 week) administration of corticosteroids at the therapeutic doses used in asthmatic patients does not modify the cutaneous reactivity to histamine, compound 48/80, or allergen. Long-term corticosteroid therapy modifies the skin texture and makes the interpretation of immediate skin tests more difficult.1

Theophylline. It appears that theophylline need not be stopped prior to skin testing.1

Beta-Blockers. Patients receiving beta-blockers may not be responsive to epinephrine or inhaled bronchodilators. The following are commonly prescribed beta-blockers: Levatol, Lopressor, Propanolol Intersol, Propanolol HCL, Blocadren, Propanolol, Inderal-LA, Visken, Corgard, Ipran, Tenormin, Timoptic. Ophthalmic beta-blockers: Betaxolol, Levobunolol, Timolol, Timoptic. Chemicals that are beta-blockers and may be components of other drugs: Acebutolol, Atenolol, Esmolol, Metoprolol, Nadolol, Penbutolol, Pindolol, Propanolol, Timolol, Labetalol, Carteolol.1

Beta-adrenergic agents. Inhaled beta2 agonists in the usual doses used for the treatment of asthma do not usually inhibit allergen-induced skin tests. However, oral terbutaline and parenteral ephedrine were shown to decrease the allergen-induced wheal.1

Cromolyn. Cromolyn inhaled or injected prior to skin tests with allergens or degranulating agents does not alter skin whealing response.1

Other drugs. Other drugs have been shown to decrease skin test reactivity. Among them, dopamine is the best-documented compound.1

Specific Immunotherapy. A decreased skin test reactivity has been observed in patients undergoing specific immunotherapy with pollen extracts, grass pollen allergoids, mites, hymenoptera venoms, or in professional beekeepers who are spontaneously desensitized. Finally, it was shown that specific immunotherapy in patients treated with ragweed pollen extract induced a decreased late-phase reaction.1

Adverse Reactions

Adverse reactions include, but are not limited to urticaria; itching; edema of extremities; respiratory wheezing or asthma; dyspnea; cyanosis; tachycardia; lacrimation; marked perspiration; flushing of face, neck or upper chest; mild persistent clearing of throat; hacking cough or persistent sneezing.

1) Local Reactions

A mild burning immediately after injection is expected; this usually subsides in 10-20 seconds. Prolonged pain or pain radiating up arm is usually the result of intramuscular injection, making this injection route undesirable. Subcutaneous injection is the recommended route.

Small amounts of erythema and swelling at the site of injection are common. Reactions should not be considered significant unless they persist for at least 24 hours or exceed 50 mm in diameter.

Larger local reactions are not only uncomfortable, but indicate the possibility of a severe systemic reaction if dosage is increased. In such cases dosage should be reduced to the last level not causing reaction and maintained for two or three treatments before cautiously increasing.

Large, persistent local reactions or minor exacerbations of the patient’s allergic symptoms may be treated by local cold applications and/or use of oral antihistamines.

2) Systemic Reactions

Systemic reactions range from mild exaggeration of patient’s allergic symptoms to anaphylactic reactions.14 Very sensitive patients may show a rapid response. It cannot be overemphasized that, under certain unpredictable combinations of circumstances, anaphylactic shock is always a possibility. Fatalities are rare but can occur.5 Other possible systemic reaction symptoms are fainting, pallor, bradycardia, hypotension, angioedema, cough, wheezing, conjunctivitis, rhinitis,and urticaria.13, 14

Careful attention to dosage and administration limit such reactions. Allergenic extracts are highly potent to sensitive individuals and OVERDOSE could result in anaphylactic symptoms. Therefore, it is imperative that physicians administering allergenic extracts understand and prepare for treatment of severe reactions. Refer to “OVERDOSAGE” section.

Overdosage

Refer to “WARNINGS”, “PRECAUTIONS” and “ADVERSE REACTIONS” sections for signs and symptoms of an overdose.

If a systemic or anaphylactic reaction does occur, apply tourniquet above the site of allergenic extract injection and inject intramuscularly or subcutaneously 0.3 to 0.5 ml of 1:1000 Epinephrine-hydrochloride into the opposite arm or gluteal area. Repeat dose in 5-10 minutes if necessary. Loosen tourniquet briefly at 5 minute intervals to prevent circulatory impairment. Discontinue use of the tourniquet after ½ hour.

The epinephrine HCL 1:1000 dose for infants to 2 years is 0.05 to 0.1 ml; for children 2 to 6 years it is 0.15 ml; for children 6 to 12 years it is 0.2 ml.

Symptoms of progressive anaphylaxis include airway obstruction and/or vascular collapse. After administration of epinephrine, profound shock and vasomotor collapse should be treated with intravenous fluids and possibly vasoactive drugs. Monitor airways for obstruction. Oxygen should be given by mask if indicated.

Antihistamines, H2 antagonist, bronchodilators, steroids and theophylline may be used as indicated after providing adequate epinephrine and circulatory support.4

Patients who have been taking beta-blockers may be unresponsive to epinephrine. Epinephrine or beta-adrenergic drugs (Alupent) may be ineffective. These drugs should be administered even though a beta-blocker may have been taken. The following treatment will be effective whether or not patient is taking a beta-blocker: Aminophylline IV, slow push or drip, Atrovent (Ipratropium bromide) Inhaler, 3 inhalations repeated, Atropine, 0.4 mg/ml, 0.75 to 1.5 ml IM or IV, Solu-Cortef, 100-200 mg IM or IV, Solu-Medrol, 125 mg IM or IV, Glucagon, 0.5-1 mg IM or IV, Benadryl, 50 mg IM or IV, Cimetidine, 300 mg IM or IV, Oxygen via ambu bag.

Allergenic Extract, Cotton,Jute,Kapok,Orris-Root,Pyrethrum,Tobacco Leaf Dosage and Administration

Refer to “STORAGE” section for proper storage condition for allergenic extract. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Some allergenic extracts naturally precipitate.

Physicians undertaking immunotherapy should be concerned with patient’s degree of sensitivity. The initial dilution of allergenic extract, starting dose, and progression of dosage must be carefully determined on the basis of the patient’s history and results of skin tests. Strongly positive skin tests may be risk factors for systemic reactions. Less aggressive immunotherapy schedules may be indicated for such patients.

Precaution is necessary when using extract mixture for skin testing. The diluting effect of individual components within a mixture may cause false negative reactions. Patients extremely sensitive to a common allergen in several components of a mixture may be more likely to experience a systemic reaction than when skin tested individually for each component.9

PRICK-PUNCTURE TESTING: To identify highly sensitive individuals and as a safety precaution, it is recommended that a prick-puncture test using a drop of the extract concentrate be performed prior to initiating very dilute intradermal testing. Prick-puncture testing is performed by placing a drop of extract concentrate on the skin and puncturing the skin through the drop with a small needle such as a bifurcated vaccinating needle. The most satisfactory sites on the back for skin testing are from the posterior axillary fold to 2.5 cm from the spinal column, and from the top of the scapula to the lower rib margins. The best areas on the arms are the volar surfaces from the axilla to 2.5 or 5 cm above the wrist, skipping the anticubital space. A positive reaction is approximately 10-15 mm erythema with 2.5 mm wheal. Smaller, less conclusive reactions may be considered positive in conjunction with a definitive history of symptoms on exposure to the allergen. The more sensitive the patient the higher the probability that he/she will have symptoms related to the exposure of the offending allergen. Hence, the importance of a good patient history. Less sensitive individuals can be tested intradermally with an appropriately diluted extract.

A positive control using histamine phosphate identifies patients whose skin may not react due to medications, metabolic or other reasons. A negative control (50% glycerine for prick-puncture testing) would exclude false-positive reactions due to ingredients in diluent or patients who have dermatographism.

SINGLE DILUTION INTRADERMAL TESTING: The surface of the upper and lower arm is the usual location for skin testing. It is important that a new, sterile, disposable syringe and needle be used for each extract tested. Intracutaneous test dilutions, five-fold or ten-fold, may be prepared from stock concentrate using physiologic saline as a diluent. (1) Start testing with the most dilute allergenic extract concentration. (2) A volume of 0.02-0.05 ml should be injected slowly into the superficial skin layers making a small bleb (superficial wheal). (3) For patients without a history of extreme sensitivity, or a negative or weakly reactive prick-puncture test, the initial dilution for skin testing should be a dilution at least 1:12,500 w/v. This initial dilution can be prepared by diluting 1:20 to 1:50 w/v (2%-5%) extracts five-fold to 5-4 or 1:10 w/v (10%) extracts to 5-5. See “Serial Dilutions Titration Test Dilutions” chart on the next page. Dilute 1:10 w/v (10%) extracts to 10-3 if using ten-fold dilutions. (4) Sensitive patients with a positive prick-puncture test require a further dilution to at least 1:312,500 w/v. This dilution can be prepared by diluting 1:20 to 1:50 w/v (2% - 5%) extracts to 5-6 or 1:10 w/v (10%) extracts to 5-7 (five-fold dilutions). Ten-fold dilution to 10-6 of a 1:10 w/v (10%) extract would be a safe starting dilution. Size of reactions are quantitated based on size of wheal and erythema. For interpretation of skin reactions, refer to chart below. If after 20 minutes no skin reaction is observed, continue testing using increasing increments of the concentration until a reaction of 5-10 mm wheal and 11-30 mm erythema is obtained, or a concentration of 5-2 or 10-1 has been tested. A negative control, 50% glycerine diluted with diluent to 5-2 (1:25) or 10-1 (1:10) dilution and a positive control of histamine phosphate, should be tested and included in interpretation of skin reactions.1, 13

GRADE	mm ERYTHEMA	mm WHEAL
0	less than 5	less than 5
±	5-10	5-10
1+	11-20	5-10
2+	21-30	5-10
3+	31-40	10-15 or with pseudopods
4+	greater than 40	greater than 15 or with many pseudopods

INTRADERMAL TESTING-SKIN ENDPOINT TITRATION: The allergenic extracts to which the patient is sensitive, the patient’s degree of sensitivity and the dose of allergen to be used in immunotherapy can be determined through the use of intracutaneous skin tests involving progressive five-fold dilutions of allergenic extracts. Intracutaneously inject 0.01 to 0.02 ml of the test allergen to form a 4 mm diameter superficial skin wheal. For patients demonstrating a negative or weakly reactive prick-puncture skin test, an initial screening dilution of 1:12,500 w/v is safe. For patients demonstrating a positive prick-puncture skin test, an initial screening dilution of 1:312,500 w/v is safe. (See “Serial Dilution Titration Test Dilutions” chart below.) When a sequence of five-fold or ten-fold dilutions of an allergen are injected, the endpoint is determined by noting the dilution that first produces a wheal and erythema (15 minutes after injection) that is 2 mm larger than wheals with erythema produced by weaker, non-reacting dilutions (5 mm negative wheal). The endpoint dilution is used as a starting dose concentration for immunotherapy. An endpoint dose of 0.15 ml is a safe initial dose to be followed by escalation to the optimal maximum tolerated dose for each individual.

Injections should never be given intravenously. A 5/8 inch, 25 gauge needle on a sterile syringe will allow deep subcutaneous injection.

IMMUNOTHERAPY: If the first injection of the initial dilution of extract is tolerated without significant local reaction, increasing doses by 5-20% increments of that dilution may be administered. The rate of increase in dosage in the early stages of treatment with highly diluted extracts is usually more rapid than the rate of increase possible with more concentrated extracts. This schedule is intended only as a guide and must be modified according to the reactivity of the individual patient. Needless to say, the physician must proceed cautiously in the treatment of the highly sensitive patient who develops large local or systemic reactions.6

Some patients may tolerate larger doses of the allergenic extract depending on patient response.7 Because diluted extract tends to lose activity in storage, the first dose from a more concentrated vial should be the same, or less than, the previous dose.8, 12

Dosages progressively increase according to the tolerance of the patient at intervals of one to seven days until, (1) the patient achieves relief from symptoms, (2) induration at the site of injection is no larger than 50 mm in 36 to 48 hours, (3) a maintenance dose is reached (the largest dose tolerated by the patient that relieves symptoms without undesirable local or systemic reactions). This maintenance dose may be continued at regular intervals perennially. It may be necessary to adjust the progression of dosage downward to avoid local and constitutional reactions.

The usual duration of treatment has not been established. A period of two or three years on immunotherapy constitutes an average minimum course of treatment.

SERIAL DILUTION TITRATION TEST DILUTIONS APPROXIMATE ALLERGENIC EXTRACT CONCENTRATION RESULTING FROM 1:5 DILUTION

Titration Number	Dilution Exponent	Weight / Volume	Allergenic Extract Concentrate
			1:50 (2%)	1:40 (2 1/2%)	1:33 1/3 (3%)	1:20 (5%)	1:10 (10%)
No. 1	5-1	1:5	1:250	1:200	1:167	1:100	1:50
No. 2	5-2	1:25	1:1,250	1:1,000	1:835	1:500	1:250
No. 3	5-3	1:125	1:6,250	1:5,000	1:4,175	1:2,500	1:1,250
No. 4	5-4	1:625	1:31,250	1:25,000	1:20,875	1:12,500	1:6,250
No. 5	5-5	1:3,125	1:156,250	1:125,000	1:104,375	1:62,500	1:31,250
No. 6	5-6	1:15,625	1:781,250	1:625,000	1:521,875	1:312,500	1:156,250
No. 7	5-7	1:78,125	1:3,906,250	1:3,125,000	1:2,609,375	1:1,562,500	1:781,250
No. 8	5-8	1:390,625	1:19,531,250	1:15,625,000	1:13,046,875	1:7,812,500	1:3,906,250
No. 9	5-9	1:1,953,125	1:97,656,250	1:78,125,000	1:65,234,375	1:39,062,500	1:19,531,250
No. 10	5-10	1:9,765,625	1:488,281,250	1:390,625,000	1:326,171,875	1:195,312,500	1:97,656,250
No. 11	5-11	1:48,828,125	1:2,441,406,250	1:1,953,125,000	1:1,630,859,375	1:976,562,500	1:488,281,250
No. 12	5-12	1:244,140,625	1:12,207,031,250	1:9,765,625,000	1:8,154,296,875	1:4,882,812,500	1:2,441,406,250

How is Allergenic Extract, Cotton,Jute,Kapok,Orris-Root,Pyrethrum,Tobacco Leaf Supplied

Stock concentrates are available in concentrations of 2-10% or weight/volume (w/v) of 1:50, 1:33, 1:20 or 1:10. Some juicy or liquid foods are available at 1:1 volume/volume (v/v) extraction ratio. Fresh egg white extract is available at 1:9 v/v extraction ratio.

Antigen E content of ragweed mixtures ranges from 46-166 U/ml for Ragweed Mixture (Short/Giant/Western/Southern Ragweed), 47-239 U/ml for Short/Giant/Western Ragweed Mixture, and 106-256 U/ml for Short/Giant Ragweed Mixture. Refer to container label for actual Antigen E content.

Extract (stock concentrate) is supplied in 10, 30 and 50 ml containers. Extracts in 5 ml dropper bottles are available for prick-puncture testing. To insure maximum potency for the entire dating period, all stock concentrates contain 50% glycerine v/v.

STORAGE

Store all stock concentrates and dilutions at 2-8° C. Keep at this temperature during office use. The expiration date of the allergenic extracts is listed on the container label. Dilutions of the allergenic extracts containing less than 50% glycerine are less stable. If loss of potency is suspected, potency can be checked using side by side skin testing with freshly prepared dilutions of equal concentration on individuals with known sensitivity to the allergen.

REFERENCES

1. Bousquet, Jean: “In vivo methods for study of allergy: Skin tests” Third Edition, Allergy Principles and Practice, C.V. Mosby Co., Vol. I, Chap. 19, pp 419-436, 1988.

2. Long, W.F., Taylor, R.J., Wagner, C.J., et al.: Skin test suppression by antihistamines and the development of subsensitivity, J. Allergy Clin. Immunol., pp. 76-113, 1985.

3. Holgate, S.T., Robinson, C., Church, Mike: Mediators of Immediate Hypersensitivity, Third Edition, Allergy Principles and Practice, C.V. Mosby Co., Vol. I and II, pp 135-163, 1988.

4. Wasserman, S., Marquart, D.: Anaphylaxis, Third Edition, Allergy Principles and Practice, C.V. Mosby Co., Vol. 1, Chap. 58, pp. 1365-1376, 1988.

5. Reid, Michael J., Lockey, Richard F., Turkeltaub M.D., Paul C., Platts-Mills, Thomas. “Survey of Fatalities from Skin Testing and Immunotherapy 1985-1989”, Journal of Allergy and Clinical Immunology, Vol. 92, No. 1, pp. 6-15, 1993.

6. Matthews, K., et al: Rhinitis, Asthma and Other Allergic Diseases. NIAID Task Force Report, U.S. Dept. HEW, NIH Publication No. 79-387, Chapter 4, pp. 213-217, May 1979.

7. Ishizaka, K.: Control of IgE Synthesis, Third Edition, Allergy Principles and Practices, Vol. I, Chap. 4, p. 52, edited by Middleton et al.

8. Nelson, H.S.: “The Effect of Preservatives and Dilution on the Deterioration of Russian Thistle (Salsola pestifer), a pollen extract.” The Journal of Allergy and Clinical Immunology, Vol. 63, No. 6, pp. 417-425, June 1979.

9. Seebohm, P.M., et al: Panel on Review of Allergenic Extracts, Final Report, Food and Drug Administration, March 13, 1981, pp. 84-86.

10. Rocklin, R.E., Sheffer, A.L., Grainader, D.K. and Melmon, K.: “Generation of antigen-specific suppressor cells during allergy desensitization”, New England Journal of Medicine, 302, May 29, 1980, pp. 1213-1219.

11. Seebohm, P.M., et al: Panel on Review of Allergenic Extracts, Final Report, Food and Drug Administration, March 13, 1981, pp 9-48.

12. Stevens, E.: Cutaneous Tests, Regulatory Control and Standardization of Allergenic Extracts, First International Paul-Ehrlich Seminar, May 20-22, 1979, Frankfurt, Germany, pp. 133-138.

13. Van Metre, T., Adkinson, N., Amodio, F., Lichtenstein, L., Mardinay, M., Norman, P., Rosenberg, G., Sobotka, A., Valentine, M.: “A Comparative Study of the Effectiveness of the Rinkel Method and the Current Standard Method of Immunology for Ragweed Pollen Hay Fever,“ The Journal of Clinical Allergy and Immunology, Vol. 66, No. 6, p. 511, December 1980.

14. Wasserman, S.: The Mast Cell and the Inflammatory Response. The Mast Cell-its role in Health and disease. Edited by J. Pepys & A.M. Edwards, Proceedings of an International Symposium, Davos, Switzerland, Pitman Medical Publishing Co., 1979, pp. 9-20.

15. Perelmutter, L.: IgE Regulation During Immunotherapy of Allergic Diseases. Annals of Allergy, Vol. 57, August 1986.

16. Bullock, J., Frick, O.: Mite Sensitivity in House Dust Allergic Children, Am. J. Dis. Child., pp. 123-222, 1972.

17. Willoughby, J.W.: Inhalant Allergy Immunotherapy with Standardized and Nonstandardized Allergenic Extracts, American Academy of Otolaryngology-Head and Neck Surgery: Instructional Courses, Vol. 1, Chapter 15, C.V. Mosby Co., St. Louis, Missouri, September 1988.

COTTON LINTERS  cotton linters  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 49288-0154 Route of Administration SUBCUTANEOUS, INTRADERMAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength COTTON FIBER (COTTON FIBER) COTTON FIBER 0.05 g  in 1 mL

Inactive Ingredients Ingredient Name Strength GLYCERIN 0.525 mL  in 1 mL SODIUM CHLORIDE 0.0095 g  in 1 mL SODIUM BICARBONATE 0.0024 g  in 1 mL WATER

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 49288-0154-1 2 mL In 1 VIAL, MULTI-DOSE None 2 49288-0154-2 5 mL In 1 VIAL, MULTI-DOSE None 3 49288-0154-3 10 mL In 1 VIAL, MULTI-DOSE None 4 49288-0154-4 30 mL In 1 VIAL, MULTI-DOSE None 5 49288-0154-5 50 mL In 1 VIAL, MULTI-DOSE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
BLA	BLA102223	03/23/1974

JUTE  jute  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 49288-0272 Route of Administration SUBCUTANEOUS, INTRADERMAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CORCORUS CAPSULARIS FIBER (CORCORUS CAPSULARIS FIBER) CORCORUS CAPSULARIS FIBER 0.05 g  in 1 mL

Inactive Ingredients Ingredient Name Strength GLYCERIN 0.525 mL  in 1 mL SODIUM CHLORIDE 0.0095 g  in 1 mL SODIUM BICARBONATE 0.0024 g  in 1 mL WATER

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 49288-0272-1 2 mL In 1 VIAL, MULTI-DOSE None 2 49288-0272-2 5 mL In 1 VIAL, MULTI-DOSE None 3 49288-0272-3 10 mL In 1 VIAL, MULTI-DOSE None 4 49288-0272-4 30 mL In 1 VIAL, MULTI-DOSE None 5 49288-0272-5 50 mL In 1 VIAL, MULTI-DOSE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
BLA	BLA102223	03/23/1974

KAPOK  kapok  injection, solution

Product Information