Drug Intercation

Yervoy 200 MG in 40 ML Injection

Generic Name: IPILIMUMAB

Brand Name: YERVOY

Substance Name(s):
IPILIMUMAB

DRUG INTERACTIONS

7 No formal pharmacokinetic drug interaction studies have been conducted with YERVOY.

OVERDOSAGE

10 There is no information on overdosage with YERVOY.

DESCRIPTION

11 YERVOY (ipilimumab) is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4).

Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa.

Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.

YERVOY is a sterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution for intravenous infusion, which may contain a small amount of visible translucent-to-white, amorphous ipilimumab particulates.

It is supplied in single-use vials of 50 mg/10 mL and 200 mg/40 mL.

Each milliliter contains 5 mg of ipilimumab and the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7.

CLINICAL STUDIES

14 14.1 Unresectable or Metastatic Melanoma The safety and efficacy of YERVOY were investigated in a randomized (3:1:1), double-blind, double-dummy trial (Trial 1) that included 676 randomized patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin.

Of these 676 patients, 403 were randomized to receive YERVOY at 3 mg/kg in combination with an investigational peptide vaccine with incomplete Freund’s adjuvant (gp100), 137 were randomized to receive YERVOY at 3 mg/kg, and 136 were randomized to receive gp100 as a single agent.

The trial enrolled only patients with HLA-A2*0201 genotype; this HLA genotype facilitates the immune presentation of the investigational peptide vaccine.

The trial excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation.

YERVOY/placebo was administered at 3 mg/kg as an intravenous infusion every 3 weeks for 4 doses.

Gp100/placebo was administered at a dose of 2 mg peptide by deep subcutaneous injection every 3 weeks for 4 doses.

Assessment of tumor response was conducted at weeks 12 and 24, and every 3 months thereafter.

Patients with evidence of objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, respectively.

The major efficacy outcome measure was overall survival (OS) in the YERVOY plus gp100 arm compared to that in the single-agent gp100 arm.

Secondary efficacy outcome measures were OS in the YERVOY plus gp100 arm compared to the YERVOY arm, OS in the YERVOY arm compared to the gp100 arm, best overall response rate (BORR) at week 24 between each of the trial arms, and duration of response.

Of the randomized patients, 61%, 59%, and 54% in the YERVOY plus gp100, YERVOY, and gp100 arms, respectively, were men.

Twenty-nine percent were ≥65 years of age, the median age was 57 years, 71% had M1c stage, 12% had a history of previously treated brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received aldesleukin, and 38% had elevated LDH level.

Sixty-one percent of patients randomized to either YERVOY-containing arm received all 4 planned doses.

The median duration of follow-up was 8.9 months.

The OS results are shown in Table 7 and Figure 1.

Table 7: Overall Survival Results a Not adjusted for multiple comparisons.

YERVOY n=137 YERVOY+gp100 n=403 gp100 n=136 Hazard Ratio (vs.

gp100) 0.66 0.68 (95% CI) (0.51, 0.87) (0.55, 0.85) p-value p=0.0026a p=0.0004 Hazard Ratio (vs.

YERVOY) 1.04 (95% CI) (0.83, 1.30) Median (months) 10 10 6 (95% CI) (8.0, 13.8) (8.5, 11.5) (5.5, 8.7) Figure 1: Overall Survival The best overall response rate (BORR) as assessed by the investigator was 5.7% (95% CI: 3.7%, 8.4%) in the YERVOY plus gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in the YERVOY arm, and 1.5% (95% CI: 0.2%, 5.2%) in the gp100 arm.

The median duration of response was 11.5 months in the YERVOY plus gp100 arm and has not been reached in the YERVOY or gp100 arm.

Figure 1 14.2 Adjuvant Treatment of Melanoma The safety and efficacy of YERVOY for the adjuvant treatment of melanoma were investigated in Trial 2, a randomized (1:1), double-blind, placebo-controlled trial in patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) histologically confirmed cutaneous melanoma.

Patients were randomized to receive YERVOY 10 mg/kg or placebo as an intravenous infusion every 3 weeks for 4 doses, followed by YERVOY 10 mg/kg or placebo every 12 weeks from Week 24 to Week 156 (3 years) or until documented disease recurrence or unacceptable toxicity.

Enrollment required complete resection of melanoma with full lymphadenectomy within 12 weeks prior to randomization.

Patients with prior therapy for melanoma, autoimmune disease, and prior or concomitant use of immunosuppressive agents were ineligible.

Randomization was stratified by stage according to American Joint Committee on Cancer (AJCC) 2002 classification (Stage IIIA >1 mm nodal involvement, Stage IIIB, Stage IIIC with 1 to 3 involved lymph nodes, and Stage IIIC with ≥4 involved lymph nodes) and by region (North America, Europe, and Australia).

The major efficacy outcome measures were recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first and assessed by an independent review committee and overall survival.

Tumor assessment was conducted every 12 weeks for the first 3 years then every 24 weeks until distant recurrence.

Among 951 patients enrolled, 475 were randomized to receive YERVOY and 476 to placebo.

Median age was 51 years old (range: 18 to 84), 62% were male, 99% were white, 94% had ECOG performance status of 0.

With regard to disease stage, 20% had Stage IIIA with lymph nodes >1 mm, 44% had Stage IIIB, and 36% had Stage IIIC (with no in-transit metastases).

Other disease characteristics of the trial population were: clinically palpable lymph nodes (58%), 2 or more positive lymph nodes (54%), and ulcerated primary lesions (42%).

The RFS results are in Table 8 and Figure 2.

Based on the observation of 282 deaths at the time of the RFS analysis, the final analysis of overall survival has not occurred (planned at the time of 491 deaths).

Table 8: Efficacy Results in Trial 2 Recurrence-Free Survival YERVOY N=475 Placebo N=476 a Stratified by disease stage.

Number of Events, n (%) Recurrence Death 234 (49%) 220 14 294 (62%) 289 5 Median (months) (95% CI) 26 (19, 39) 17 (13, 22) Hazard Ratio (95% CI) p-value (stratified log-ranka) 0.75 (0.64, 0.90) p<0.002 Figure 2: Recurrence-Free Survival Recurrenc-Free Survival

HOW SUPPLIED

16 /STORAGE AND HANDLING YERVOY is available as follows: Carton Contents NDC One 50 mg vial (5 mg/mL), single-use vial NDC 0003-2327-11 One 200 mg vial (5 mg/mL), single-use vial NDC 0003-2328-22 Store YERVOY under refrigeration at 2°C to 8°C (36°F to 46°F).

Do not freeze.

Protect vials from light.

GERIATRIC USE

8.5 Geriatric Use Of the 511 patients treated with YERVOY in Trial 1, 28% were 65 years and over.

No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).

Trial 2 did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

DOSAGE FORMS AND STRENGTHS

3 Injection: 50 mg/10 mL (5 mg/mL) Injection: 200 mg/40 mL (5 mg/mL) •Injection: 50 mg/10 mL (5 mg/mL) (3) •Injection: 200 mg/40 mL (5 mg/mL) (3)

MECHANISM OF ACTION

12.1 Mechanism of Action CTLA-4 is a negative regulator of T-cell activity.

Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86.

Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells.

Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T cell responsiveness, including the anti-tumor immune response.

INDICATIONS AND USAGE

1 YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for: •Treatment of unresectable or metastatic melanoma.

(1.1) •Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.

(1.2) 1.1 Unresectable or Metastatic Melanoma YERVOY is indicated for the treatment of unresectable or metastatic melanoma [see Clinical Studies (14.1)].

1.2 Adjuvant Treatment of Melanoma YERVOY is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy [see Clinical Studies (14.2)].

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of YERVOY have not been established in pediatric patients.

PREGNANCY

8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].

In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner (see Data).

The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy.

Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.

There is insufficient human data for YERVOY exposure in pregnant women.

Advise pregnant women of the potential risk to a fetus.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

A Pregnancy Safety Surveillance Study has been established to collect information about pregnancies in women who have received YERVOY.

Healthcare providers are encouraged to enroll patients or have their patients enroll directly by calling 1-844-593-7869.

Data Animal Data In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition.

No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy.

Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at a dose of 3 mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality.

In addition, developmental abnormalities were identified in the urogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the AUC in humans at the 3 mg/kg dose).

One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema.

Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/−), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/− heterozygous offspring.

Mated CTLA-4+/− heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4−/−).

The CTLA-4−/− homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3 to 4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction.

BOXED WARNING

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions.

These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy.

The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions [see Dosage and Administration (2.3) ].

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries including liver function tests, adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5)].

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS See full prescribing information for complete boxed warning.

YERVOY can result in severe and fatal immune-mediated adverse reactions.

The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

(2.3) Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

(5.1, 5.2, 5.3, 5.4, 5.5)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS YERVOY can result in severe and fatal immune-mediated reactions [see Boxed Warning].

Immune-mediated adverse reactions: Permanently discontinue for severe reactions.

Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving less than 7.5 mg prednisone or equivalent per day.

Administer systemic high-dose corticosteroids for severe, persistent, or recurring immune-mediated reactions.

(5.1, 5.2, 5.3, 5.4, 5.5) •Immune-mediated hepatitis: Evaluate liver function tests before each dose of YERVOY.

(5.2) •Immune-mediated endocrinopathies: Monitor clinical chemistries, ACTH level, and thyroid function tests prior to each dose.

Evaluate at each visit for signs and symptoms of endocrinopathy.

Institute hormone replacement therapy as needed.

(5.5) •Embryo-fetal toxicity: Can cause fetal harm.

Advise of potential risk to a fetus and use of effective contraception.

(5.7) 5.1 Immune-Mediated Enterocolitis Immune-mediated enterocolitis, including fatal cases, can occur with YERVOY.

Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus).

In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.

Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.

Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.

In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients.

Consider adding anti-TNF or other immunosuppressant agents for management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3 to 5 days or recurring after symptom improvement.

Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent [see Dosage and Administration (2.3)].

Metastatic Melanoma In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3 to 5) immune-mediated enterocolitis occurred in 34 YERVOY-treated patients (7%), and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%).

Across all YERVOY-treated patients (n=511), 5 patients (1%) developed intestinal perforation, 4 patients (0.8%) died as a result of complications, and 26 patients (5%) were hospitalized for severe enterocolitis.

The median time to onset of Grade 3 to 5 enterocolitis was 1.7 months (range: 11 days to 3.1 months) and for Grade 2 enterocolitis was 1.4 months (range: 2 days to 4.3 months).

Twenty-nine patients (85%) with Grade 3 to 5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 16 days (ranging up to 3.2 months) followed by corticosteroid taper.

Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 1.2 months, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper.

Infliximab was administered to 5 (8%) of the 62 patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.

Of the 34 patients with Grade 3 to 5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve.

Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.

Adjuvant Treatment of Melanoma In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 5 immune-mediated enterocolitis occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in 68 patients (14%).

Seven patients (1.5%) developed intestinal perforation and 3 patients (0.6%) died as a result of complications [see Adverse Reactions (6.1)].

The median time to onset for Grade 3 to 4 enterocolitis was 1.1 months (range: 1 day to 33.1 months) and for Grade 2 enterocolitis was 1.1 months (range: 1 day to 20.6 months).

Seventy-one patients (95%) with Grade 3 to 4 enterocolitis were treated with systemic corticosteroids.

The median duration of treatment was 4.7 months (ranging up to 52.3 months).

Of the 68 patients with moderate enterocolitis, 51 patients (75%) were treated with systemic corticosteroids with a median duration of treatment of 3.5 months (ranging up to 52.2 months).

Non-corticosteroids immunosuppression, consisting almost exclusively of infliximab, was used to treat 36% of patients with Grade 3 to 4 enterocolitis and 15% of patients with a Grade 2 event.

Of the 75 patients with Grade 3 to 4 immune-mediated enterocolitis, 86% experienced complete resolution, 3% experienced improvement to Grade 1, and 11% did not improve.

Among the 68 patients with Grade 2 enterocolitis, 94% experienced complete resolution, 3% experienced improvement to Grade 1, and 3% did not improve.

5.2 Immune-Mediated Hepatitis Immune-mediated hepatitis, including fatal cases, can occur with YERVOY.

Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY.

In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.

Permanently discontinue YERVOY in patients with Grade 3 to 4 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.

When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month.

Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids.

Withhold YERVOY in patients with Grade 2 hepatotoxicity [see Dosage and Administration (2.3) ].

Metastatic Melanoma In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3 to 5) occurred in 8 YERVOY-treated patients (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients.

An additional 13 patients (2.5%) experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2).

The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis.

There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.

Adjuvant Treatment of Melanoma In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated hepatitis occurred in 51 patients (11%) and moderate Grade 2 immune-mediated hepatitis occurred in 22 patients (5%).

Liver biopsy performed in 6 patients with Grade 3 to 4 hepatitis showed evidence of toxic or autoimmune hepatitis.

The median time to onset for Grade 3 to 4 hepatitis was 2.0 months (range: 1 day to 4.2 months) and for Grade 2 hepatitis was 1.4 months (range: 13 days to 6.5 months).

Of the 51 patients with Grade 3 to 4 immune-mediated hepatitis, 94% experienced complete resolution, 4% experienced improvement to Grade 1, and 2% did not improve.

Of the 22 patients with Grade 2 immune-mediated hepatitis, 91% experienced complete resolution and 9% did not improve.

Forty-six patients (90%) with Grade 3 to 4 hepatitis were treated with systemic corticosteroids.

The median duration of treatment was 4.4 months (ranging up to 56.1 months).

Sixteen patients (73%) with moderate hepatitis were treated with systemic corticosteroids.

The median duration of treatment was 2.6 months (ranging up to 41.4 months).

Concurrent Administration with Vemurafenib In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID).

5.3 Immune-Mediated Dermatitis Immune-mediated dermatitis, including fatal cases, can occur with YERVOY.

Monitor patients for signs and symptoms of dermatitis, such as rash and pruritus.

Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.

Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations.

Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.

When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month.

Withhold YERVOY dosing in patients with moderate to severe signs and symptoms [see Dosage and Administration (2.3) ].

For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically.

Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.

Metastatic Melanoma In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3 to 5) occurred in 13 YERVOY-treated patients (2.5%).

One patient (0.2%) died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis.

There were 63 patients (12%) with moderate (Grade 2) dermatitis.

The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 22 days and ranged up to 4.0 months from the initiation of YERVOY.

Seven YERVOY-treated patients (54%) with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 3.4 months followed by corticosteroid taper.

Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 3.6 months.

Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 15 days, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids.

Forty-four patients (70%) with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.

Adjuvant Treatment of Melanoma In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated dermatitis occurred in 19 patients (4%).

There were 99 patients (21%) with moderate (Grade 2) dermatitis.

The median time to onset for Grade 3 to 4 dermatitis was 14 days (range: 5 days to 11.3 months) and for Grade 2 dermatitis was 11 days (range: 1 day to 16.6 months).

Sixteen patients (84%) with Grade 3 to 4 dermatitis were treated with systemic corticosteroids for a median of 21 days (ranging up to 49.2 months) resulting in complete resolution of dermatitis within a median time of 4.3 months (range up to 44.4 months).

Of the 3 patients (16%) not treated with systemic or topical corticosteroids, 2 (11%) had complete resolution and 1 had improvement to Grade 1.

Of the 99 patients with Grade 2 dermatitis, 67 (68%) were treated with systemic corticosteroids for a median of 2.6 months, 16 (16%) were treated with only topical corticosteroids and 16 (16%) did not receive systemic or topical corticosteroids.

Seventy-seven patients (78%) had complete resolution, 15 (15%) improved to mild (Grade 1) severity, and 7 (7%) did not improve.

5.4 Immune-Mediated Neuropathies Immune-mediated neuropathies, including fatal cases, can occur with YERVOY.

Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia.

Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes.

Institute medical intervention as appropriate for management of severe neuropathy.

Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies.

Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities) [see Dosage and Administration (2.3)].

Metastatic Melanoma In patients receiving YERVOY 3 mg/kg in Trial 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.

Adjuvant Treatment of Melanoma In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 5 immune-mediated neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of Guillain-Barré syndrome [see Adverse Reactions (6.1) ].

Moderate Grade 2 immune-mediated neuropathy occurred in 1 patient (0.2%).

The time to onset across the 9 patients with Grade 2 to 5 immune-mediated neuropathy ranged from 1.4 to 27.4 months.

All 8 patients with Grade 3 to 5 neuropathy were treated with systemic corticosteroids (range: 3 days to 38.3 months) and 3 also received tacrolimus.

Four of the 8 patients with Grade 3 to 5 immune-mediated neuropathy experienced complete resolution, 1 improved to Grade 1, and 3 did not improve.

The single patient with Grade 2 immune-mediated neuropathy experienced complete resolution without the use of corticosteroids.

5.5 Immune-Mediated Endocrinopathies Immune-mediated endocrinopathies, including life-threatening cases, can occur with YERVOY.

Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism.

Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease.

Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.

Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at the start of treatment, before each dose, and as clinically indicated based on symptoms.

In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.

Withhold YERVOY dosing in symptomatic patients and consider referral to an endocrinologist.

Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy [see Dosage and Administration (2.3) ].

Metastatic Melanoma In patients receiving YERVOY 3 mg/kg in Trial 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3 to 4) occurred in 9 YERVOY-treated patients (1.8%).

All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism.

Six of the 9 patients were hospitalized for severe endocrinopathies.

Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome.

The median time to onset of moderate to severe immune-mediated endocrinopathy was 2.5 months and ranged up to 4.4 months after the initiation of YERVOY.

Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).

Adjuvant Treatment of Melanoma In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated endocrinopathies occurred in 39 patients (8%) and Grade 2 immune-mediated endocrinopathies in 93 patients (20%).

Of the 39 patients with Grade 3 to 4 immune-mediated endocrinopathies, 35 patients had hypopituitarism (associated with one or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism.

The median time to onset of Grade 3 to 4 immune-mediated endocrinopathy was 2.2 months (range: 2 days to 8 months).

Twenty-seven of the 39 patients (69%) were hospitalized for immune-mediated endocrinopathies, and 4 patients (10%) were reported to have resolution.

Of the 93 patients with Grade 2 immune-mediated endocrinopathy, 74 had primary hypopituitarism (associated with one or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 9 had primary hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo- or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’ ophthalmopathy.

The median time to onset of Grade 2 immune-mediated endocrinopathy was 2.1 months (range: 9 days to 19.3 months), and 20% were reported to have resolution.

One hundred twenty-four patients received systemic corticosteroids as immunosuppression and/or adrenal hormone replacement for Grade 2 to 4 immune-mediated endocrinopathy.

Of these, 42 (34%) were able to discontinue corticosteroids.

Seventy-three patients received thyroid hormones for treatment of Grade 2 to 4 immune-mediated hypothyroidism.

Of these, 14 patients (19%) were able to discontinue thyroid replacement therapy.

5.6 Other Immune-Mediated Adverse Reactions, Including Ocular Manifestations Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions.

Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.

Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis.

Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy [see Dosage and Administration (2.3) ].

Metastatic Melanoma In Trial 1, the following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.

Adjuvant Treatment of Melanoma In Trial 2, the following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients unless specified: eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis, and fatal myocarditis [see Adverse Reactions (6.1)].

Other Clinical Experience Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478), the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis, hemolytic anemia, and nephritis.

5.7 Embryo-fetal Toxicity Based on its mechanism of action and data from animal studies, YERVOY can cause fetal harm when administered to a pregnant woman.

The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy.

Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with a YERVOY-containing regimen and for 3 months after the last dose of YERVOY [see Use in Specific Populations (8.1, 8.3)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Immune-Mediated Adverse Reactions Inform patients of the potential risk of immune-mediated adverse reactions [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6)].

Embryo-fetal Toxicity Advise female patients that YERVOY can cause fetal harm.

Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months after the last dose.

Advise female patients to contact their healthcare provider with a known or suspected pregnancy.

Advise females who may have been exposed to YERVOY during pregnancy to contact Bristol-Myers Squibb at 1-800-721-5072 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].

Advise patients that there is a Pregnancy Safety Surveillance Study that monitors pregnancy outcomes in women exposed to YERVOY during pregnancy, and they can be enrolled by calling 1-844-593-7869 [see Use in Specific Populations (8.1)].

Lactation Advise women not to breastfeed during treatment with YERVOY and for 3 months after the last dose [see Use in Specific Populations (8.2)].

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S.

License No.

1713 1281558B0

DOSAGE AND ADMINISTRATION

2 •Unresectable or metastatic melanoma: ∘3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses.

(2.1) •Adjuvant melanoma: ∘10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicity.

(2.2) •Permanently discontinue for severe adverse reactions.

(2.3) 2.1 Recommended Dosing for Unresectable or Metastatic Melanoma The recommended dose of YERVOY is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a maximum of 4 doses.

In the event of toxicity, doses may be delayed, but all treatment must be administered within 16 weeks of the first dose [see Clinical Studies (14.1)].

2.2 Recommended Dosing for Adjuvant Treatment of Melanoma The recommended dose of YERVOY is 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years [see Clinical Studies (14.2)].

In the event of toxicity, doses are omitted, not delayed.

2.3 Recommended Dose Modifications Table 1: Recommended Treatment Modifications for Immune-Mediated Adverse Reactions of YERVOY Target/Organ System Adverse Reaction (CTCAE v3) Treatment Modification Endocrine Symptomatic endocrinopathy Withhold YERVOY Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0 to 1) and who are receiving less than 7.5 mg prednisone or equivalent per day.

•Symptomatic reactions lasting 6 weeks or longer •Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day Permanently discontinue YERVOY Ophthalmologic Grade 2 through 4 reactions •not improving to Grade 1 within 2 weeks while receiving topical therapy or •requiring systemic treatment Permanently discontinue YERVOY All Other Grade 2 Withhold YERVOY Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0 to 1) and who are receiving less than 7.5 mg prednisone or equivalent per day.

•Grade 2 reactions lasting 6 weeks or longer •Inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day •Grade 3 or 4 Permanently discontinue YERVOY 2.4 Preparation and Administration •Do not shake product.

•Inspect parenteral drug products visually for particulate matter and discoloration prior to administration.

Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles.

Preparation of Solution •Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation of infusion.

•Withdraw the required volume of YERVOY and transfer into an intravenous bag.

•Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL.

Mix diluted solution by gentle inversion.

•Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F).

•Discard partially used vials or empty vials of YERVOY.

Administration Instructions •Do not mix YERVOY with, or administer as an infusion with, other medicinal products.

•Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose.

•Administer diluted solution over 90 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in-line filter.

ketamine (as ketamine hydrochloride) 100 MG/ML Injectable Solution

No Details Found

Undecylenic Acid 50 MG/ML / Zinc undecylenate 180 MG/ML Topical Cream [Derman Antifungal Cream]

Generic Name: ZINC UNDECYLENATE

Brand Name: Derman Antifungal

Substance Name(s):
ZINC UNDECYLENATE
UNDECYLENIC ACID

WARNINGS

Warnings For external use only Do not use on children under 2 years of age, unless directed by a doctor.

When using this product Avoid contact with the eyes.

Stop use and ask a doctor if irritation occurs or if there is no improvement within 4 weeks.

Keep out of the reach of children.

If swallowed, get medical help or contact a Poison Control Center right away.

INDICATIONS AND USAGE

Uses For the treatment of athlete´s foot.

INACTIVE INGREDIENTS

Inactive Ingredients Cetyl, Glycerin, Polyethylene Glycol 500, Polyethylene Glycol 4000, Water, Glycerin, Cetyl Alcohol, Propylene Glycol, Sodium Bisulfite, Sodium laureth Sulfate, water, Zinc Stearate.

PURPOSE

Purpose Antifungal

KEEP OUT OF REACH OF CHILDREN

Keep out of the reach of children.

If swallowed, get medical help or contact a Poison Control Center right away.

DOSAGE AND ADMINISTRATION

Directions Wash the affected area and dry thoroughly.

Apply a thin layer of the product over the affected area twice daily (morning and night) or as directed by a physician.

Supervise children in the use of this product.

Pay special attention to spaces between the toes, wear well fitting, ventilated shoes.

Change shoes and socks at least once daily.

Use daily for 4 weeks.

If condition persists, consults a physician.

This product is not effective on the scalp or nails.

DO NOT USE

Do not use Do not use on children under 2 years of age, unless directed by a doctor.

ACTIVE INGREDIENTS

Active Ingredients.

Zinc undecylenate 18% Undecylenic acid 5%

Ketamine 100 MG/ML Injectable Solution [Ketaset]

No Details Found

Jantoven 1 MG Oral Tablet

DRUG INTERACTIONS

7 Drugs may interact with JANTOVEN through pharmacodynamic or pharmacokinetic mechanisms.

Pharmacodynamic mechanisms for drug interactions with JANTOVEN are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance).

Pharmacokinetic mechanisms for drug interactions with JANTOVEN are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding.

It is important to note that some drugs may interact by more than one mechanism.

More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use (e.g., antibiotics, antifungals, corticosteroids) [see Boxed Warning ].

Consult the labeling of all concurrently used drugs to obtain further information about interactions with JANTOVEN or adverse reactions pertaining to bleeding.

Consult labeling of all concurrently used drugs for complete information about interactions with JANTOVEN or increased risks for bleeding.

(7) Inhibitors and inducers of CYP2C9, 1A2, or 3A4: May alter warfarin exposure.

Monitor INR closely when any such drug is used with JANTOVEN.

(7.1) Drugs that increase bleeding risk: Closely monitor patients receiving any such drug (e.g., other anticoagulants, antiplatelet agents, nonsteroidal antiinflammatory drugs, serotonin reuptake inhibitors).

(7.2) Antibiotics and antifungals: Closely monitor INR when initiating or stopping an antibiotic or antifungal course of therapy.

(7.3) Botanical (herbal) products: Some may influence patient response to JANTOVEN necessitating close INR monitoring.

(7.4) 7.1 CYP450 Interactions CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4.

The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4.

Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin.

Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin.

Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive.

Consult the labeling of all concurrently used drugs to obtain further information about CYP450 interaction potential.

The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant medications.

Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer.

Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.2 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3.

Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin.

Table 3: Drugs that Can Increase the Risk of Bleeding Drug Class Specific Drugs Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 7.3 Antibiotics and Antifungals There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin.

Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin.

7.4 Botanical (Herbal) Products and Foods Exercise caution when botanical (herbal) products are taken concomitantly with JANTOVEN.

Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium exist.

Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary.

This could further confound the ability to assess potential interactions and effects on anticoagulation.

Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties.

These effects would be expected to be additive to the anticoagulant effects of JANTOVEN.

Conversely, some botanicals may decrease the effects of JANTOVEN (e.g., co-enzyme Q10, St.

John’s wort ginseng).

Some botanicals and foods can interact with JANTOVEN through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St.

John’s wort).

Monitor the patient’s response with additional INR determinations when initiating or discontinuing any botanicals.

OVERDOSAGE

10 10.1 Signs and Symptoms Bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in hemoglobin) is a manifestation of excessive anticoagulation.

10.2 Treatment The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances.

Reversal of JANTOVEN anticoagulation may be obtained by discontinuing JANTOVEN therapy and, if necessary, by administration of oral or parenteral vitamin K1.

The use of vitamin K1 reduces response to subsequent JANTOVEN therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR.

Resumption of JANTOVEN administration reverses the effect of vitamin K, and a therapeutic INR can again be obtained by careful dosage adjustment.

If rapid re-anticoagulation is indicated, heparin may be preferable for initial therapy.

Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of JANTOVEN is urgent.

A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis.

Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to JANTOVEN overdosage.

DESCRIPTION

11 JANTOVEN (Warfarin Sodium Tablets, USP) is an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors.

Chemically, it is 3-(α-acetonylbenzyl)-4-hydroxycoumarin and is a racemic mixture of the R- and S-enantiomers.

Its empirical formula is C19H15NaO4, and its structural formula is represented by the following: Warfarin sodium occurs as a white, odorless powder that is discolored by light.

It is very soluble in water, freely soluble in alcohol, and very slightly soluble in chloroform and ether.

JANTOVEN tablets for oral use contain: 1 mg, 2 mg, 2½ mg, 3 mg, 4 mg, 5 mg, 6 mg, 7½ mg or 10 mg of warfarin sodium, USP.

They also contain: All strengths: Lactose monohydrate, magnesium stearate, povidone, and pregelatinized starch (corn).

1 mg: FD&C Red #40 Aluminum Lake 2 mg: FD&C Blue #2 Aluminum Lake and FD&C Red #40 Aluminum Lake 2½ mg: D&C Yellow #10 Aluminum Lake and FD&C Blue #1 Aluminum Lake 3 mg: Brown #75 Synthetic Brown Iron Oxide 4 mg: FD&C Blue #1 Aluminum Lake 5 mg: FD&C Yellow #6 Aluminum Lake 6 mg: Yellow #10 Synthetic Yellow Iron Oxide, Black #85 Synthetic Black Iron Oxide and FD&C Blue #1 Aluminum Lake 7½ mg: D&C Yellow #10 Aluminum Lake and FD&C Yellow #6 Aluminum Lake 10 mg: Dye Free Chemical Structure

CLINICAL STUDIES

14 14.1 Atrial Fibrillation In five prospective, randomized, controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 4).

The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was stopped early due to published positive results from two of these trials.

The incidence of major bleeding in these trials ranged from 0.6% to 2.7% (see Table 4).

Table 4: Clinical Studies of Warfarin in Non-Rheumatic AF PatientsAll study results of warfarin vs.

control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhagic stroke and transient ischemic attacks.

N Thromboembolism % Major Bleeding Study Warfarin- Treated Patients Control Patients PT Ratio INR % Risk Reduction p-value Warfarin- Treated Patients Control Patients AFASAK 335 336 1.5-2.0 2.8-4.2 60 0.027 0.6 0.0 SPAF 210 211 1.3-1.8 2.0-4.5 67 0.01 1.9 1.9 BAATAF 212 208 1.2-1.5 1.5-2.7 86 <0.05 0.9 0.5 CAFA 187 191 1.3-1.6 2.0-3.0 45 0.25 2.7 0.5 SPINAF 260 265 1.2-1.5 1.4-2.8 79 0.001 2.3 1.5 Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with warfarin sodium [see Dosage and Administration (2.2) ].

14.2 Mechanical and Bioprosthetic Heart Valves In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirin treated patients (p<0.005) and pentoxifylline/aspirin-treated patients (p<0.05).

The results of this study are presented in Table 5.

Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Patients Treated With Event Warfarin Dipyridamole/Aspirin Pentoxifylline/Aspirin py=patient years Thromboembolism 2.2/100 py 8.6/100 py 7.9/100 py Major Bleeding 2.5/100 py 0.0/100 py 0.9/100 py In a prospective, open-label, clinical study comparing moderate (INR 2.65) vs.

high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events per 100 patient years, respectively).

Major bleeding was more common in the high intensity group.

The results of this study are presented in Table 6.

Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Event Moderate Warfarin Therapy INR 2.65 High Intensity Warfarin Therapy INR 9.0 py=patient years Thromboembolism 4.0/100 py 3.7/100 py Major Bleeding 0.95/100 py 2.1/100 py In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25 vs.

INR 2.5-4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs.

1.9%, respectively, and minor embolic events 10.8% vs.

10.2%, respectively).

Major hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group.

14.3 Myocardial Infarction WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8.

The primary endpoint was a composite of total mortality and recurrent infarction.

A secondary endpoint of cerebrovascular events was assessed.

Mean follow-up of the patients was 37 months.

The results for each endpoint separately, including an analysis of vascular death, are provided in Table 7: Table 7: WARIS – Endpoint Analysis of Separate Events Event Warfarin (N=607) Placebo (N=607) RR (95% CI) % Risk Reduction (p-value) RR=Relative risk; Risk reduction=(1 – RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years Total Patient Years of Follow-up 2018 1944 Total Mortality 94 (4.7/100 py) 123 (6.3/100 py) 0.76 (0.60, 0.97) 24 (p=0.030) Vascular Death 82 (4.1/100 py) 105 (5.4/100 py) 0.78 (0.60, 1.02) 22 (p=0.068) Recurrent MI 82 (4.1/100 py) 124 (6.4/100 py) 0.66 (0.51, 0.85) 34 (p=0.001) Cerebrovascular Event 20 (1.0/100 py) 44 (2.3/100 py) 0.46 (0.28, 0.75) 54 (p=0.002) WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin to a target INR 2.8 to 4.2, aspirin 160 mg per day, or warfarin to a target INR 2.0 to 2.5 plus aspirin 75 mg per day prior to hospital discharge.

The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke.

The mean duration of observation was approximately 4 years.

The results for WARIS II are provided in the Table 8.

Table 8: WARIS II – Distribution of Events According to Treatment Group Event Aspirin (N=1206) Warfarin (N=1216) Aspirin plus Warfarin (N=1208) Rate Ratio (95% CI) p-value CI=confidence interval ND=not determined No.

of Events Major BleedingMajor bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion.

8 33 28 3.35The rate ratio is for aspirin plus warfarin as compared with aspirin.

(ND) 4.00The rate ratio is for warfarin as compared with aspirin.

(ND) ND ND Minor BleedingMinor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion.

39 103 133 3.21 (ND) 2.55 (ND) ND ND Composite EndpointsIncludes death, nonfatal reinfarction, and thromboembolic cerebral stroke.

241 203 181 0.81 (0.69-0.95) 0.71 (0.60-0.83) 0.03 0.001 Reinfarction 117 90 69 0.56 (0.41-0.78) 0.74 (0.55-0.98) <0.001 0.03 Thromboembolic Stroke 32 17 17 0.52 (0.28-0.98) 0.52 (0.28-0.97) 0.03 0.03 Death 92 96 95 0.82 There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone.

Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group.

HOW SUPPLIED

16 /STORAGE AND HANDLING Tablets JANTOVEN tablets are single scored, compressed tablets with one side scored and debossed with WRF above the score and 1, 2, 2½, 3, 4, 5, 6, 7½, or 10 below the score and with 832 debossed on the opposite side.

JANTOVEN is available in bottles and unit-dose blister packages with potencies and colors as follows: 1 mg – Compressed tablet, pink, round; in bottles of 100 (NDC 0832-1211-00) and 1000 (NDC 0832-1211-10) and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each) (NDC 0832-1211-01).

2 mg – Compressed tablet, lavender, round; in bottles of 100 (NDC 0832-1212-00) and 1000 (NDC 0832-1212-10) and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each) (NDC 0832-1212-01).

2½ mg -Compressed tablet, green, round; in bottles of 100 (NDC 0832-1213-00) and 1000 (NDC 0832-1213-10) and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each) (NDC 0832-1213-01).

3 mg – Compressed tablet, tan, round; in bottles of 100 (NDC 0832-1214-00) and 1000 (NDC 0832-1214-10) and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each) (NDC 0832-1214-01).

4 mg – Compressed tablet, blue, round; in bottles of 100 (NDC 0832-1215-00) and 1000 (NDC 0832-1215-10) and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each) (NDC 0832-1215-01).

5 mg – Compressed tablet, peach, round; in bottles of 100 (NDC 0832-1216-00) and 1000 (NDC 0832-1216-10) and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each) (NDC 0832-1216-01).

6 mg – Compressed tablet, teal, round; in bottles of 100 (NDC 0832-1217-00) and 1000 (NDC 0832-1217-10) and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each) (NDC 0832-1217-01).

7½ mg – Compressed tablet, yellow, round; in bottles of 100 (NDC 0832-1218-00) and 500 (NDC 0832-1218-50) and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each) (NDC 0832-1218-01).

10 mg – Compressed tablet, white, round; in bottles of 100 (NDC 0832-1219-00) and 500 (NDC 0832-1219-50) and in unit dose cartons of 100 tablets (10 cards containing 10 tablets each) (NDC 0832-1219-01).

Store at 20 to 25°C (68 to 77°F).

Excursions permitted to 15 to 30°C (59 to 86°F).

[See USP Controlled Room Temperature.] Protect from light and moisture.

Dispense in a tight, light-resistant container with a child-resistant closure.

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older.

No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see Clinical Pharmacology (12.3) ].

JANTOVEN is contraindicated in any unsupervised patient with senility.

Observe caution with administration of JANTOVEN to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present.

Consider lower initiation and maintenance doses of JANTOVEN in elderly patients [see Dosage and Administration (2.2, 2.3) ].

DOSAGE FORMS AND STRENGTHS

3 JANTOVEN tablets are single scored, compressed tablets with one side scored and debossed with WRF above the score and 1, 2, 2½, 3, 4, 5, 6, 7½, or 10 below the score and with 832 debossed on the opposite side.

JANTOVEN tablets are supplied in the following strengths: JANTOVEN Tablets Strength Color 1 mg pink 2 mg lavender 2½ mg green 3 mg tan 4 mg blue 5 mg peach 6 mg teal 7½ mg yellow 10 mg white (dye-free) Scored tablets: 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2, or 10 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S.

Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors.

Vitamin K promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins that are essential for biological activity.

Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide [see Clinical Pharmacology (12.5) ].

INDICATIONS AND USAGE

1 JANTOVEN® is indicated for: Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE).

Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement.

Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

Limitations of Use Warfarin Sodium has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage.

Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae.

JANTOVEN is a vitamin K antagonist indicated for: Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (1) Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement (1) Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction (1) Limitation of Use Warfarin Sodium has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage.

(1)

PEDIATRIC USE

8.4 Pediatric Use Adequate and well-controlled studies with warfarin sodium have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown.

Pediatric use of warfarin sodium is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries.

Pediatric patients administered JANTOVEN should avoid any activity or sport that may result in traumatic injury.

The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants.

Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs.

Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended.

Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries.

Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.

PREGNANCY

8.1 Pregnancy Pregnancy Category D for women with mechanical heart valves [see Warnings and Precautions (5.5) ] and Pregnancy Category X for other pregnant populations [see Contraindications (4) ].

JANTOVEN is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of JANTOVEN may outweigh the risks.

JANTOVEN can cause fetal harm when administered to a pregnant woman.

JANTOVEN exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy), fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality.

The reproductive and developmental effects of warfarin sodium have not been evaluated in animals.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values.

Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring.

Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight).

Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy.

Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy [see Contraindications (4) and Warnings and Precautions (5.6) ].

NUSRING MOTHERS

8.3 Nursing Mothers Based on published data in 15 nursing mothers, warfarin was not detected in human milk.

Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range.

Prothrombin times were not obtained for the other 9 nursing infants.

Monitor breast-feeding infants for bruising or bleeding.

Effects in premature infants have not been evaluated.

Caution should be exercised when JANTOVEN is administered to a nursing woman.

BOXED WARNING

WARNING: BLEEDING RISK Warfarin Sodium can cause major or fatal bleeding [see Warnings and Precautions (5.1) ].

Perform regular monitoring of INR in all treated patients [see Dosage and Administration (2.1) ].

Drugs, dietary changes, and other factors affect INR levels achieved with Warfarin Sodium therapy [see Drug Interactions (7) ].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ].

WARNING: BLEEDING RISK See full prescribing information for complete boxed warning.

Warfarin Sodium can cause major or fatal bleeding.

(5.1) Perform regular monitoring of INR in all treated patients.

(2.1) Drugs, dietary changes, and other factors affect INR levels achieved with Warfarin Sodium therapy.

(7) Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding.

(17)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation.

Discontinue JANTOVEN and consider alternative anticoagulants if necessary.

(5.2) Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death.

Discontinue JANTOVEN if such emboli occur.

(5.3) Heparin-induced thrombocytopenia (HIT): Initial therapy with Warfarin Sodium in HIT has resulted in cases of amputation and death.

Warfarin Sodium may be considered after platelet count has normalized.

(5.4) Pregnant women with mechanical heart valves: Warfarin Sodium may cause fetal harm; however, the benefits may outweigh the risks.

(5.5) 5.1 Hemorrhage JANTOVEN can cause major or fatal bleeding.

Bleeding is more likely to occur within the first month.

Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see Clinical Pharmacology (12.5) ], certain concomitant drugs [see Drug Interactions (7) ], and long duration of warfarin therapy.

Perform regular monitoring of INR in all treated patients.

Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition.

However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.

Drugs, dietary changes, and other factors affect INR levels achieved with JANTOVEN therapy.

Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions (7) ].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ].

5.2 Tissue Necrosis Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (<0.1%).

Necrosis may be associated with local thrombosis and usually appears within a few days of the start of JANTOVEN therapy.

In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.

Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease.

Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective.

Discontinue JANTOVEN therapy if necrosis occurs.

Consider alternative drugs if continued anticoagulation therapy is necessary.

5.3 Systemic Atheroemboli and Cholesterol Microemboli Anticoagulation therapy with JANTOVEN may enhance the release of atheromatous plaque emboli.

Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization.

The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver.

Some cases have progressed to necrosis or death.

A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue JANTOVEN therapy if such phenomena are observed.

Consider alternative drugs if continued anticoagulation therapy is necessary.

5.4 Heparin-Induced Thrombocytopenia Do not use JANTOVEN as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS).

Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued.

In some patients, sequelae have included amputation of the involved area and/or death.

Treatment with JANTOVEN may be considered after the platelet count has normalized.

5.5 Use in Pregnant Women with Mechanical Heart Valves JANTOVEN can cause fetal harm when administered to a pregnant woman.

While JANTOVEN is contraindicated during pregnancy, the potential benefits of using JANTOVEN may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism.

In those individual situations, the decision to initiate or continue JANTOVEN should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines.

JANTOVEN exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1) ].

5.6 Females of Reproductive Potential JANTOVEN exposure during pregnancy can cause pregnancy loss, birth defects, or fetal death.

Discuss pregnancy planning with females of reproductive potential who are on JANTOVEN therapy [see Contraindications (4) and Use in Specific Populations (8.8) ].

5.7 Other Clinical Settings with Increased Risks In the following clinical settings, the risks of JANTOVEN therapy may be increased: Moderate to severe hepatic impairment Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy) Use of an indwelling catheter Severe to moderate hypertension Deficiency in protein C-mediated anticoagulant response: JANTOVEN reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S.

Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration.

Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with JANTOVEN may minimize the incidence of tissue necrosis in these patients.

Eye surgery: In cataract surgery, JANTOVEN use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications.

As JANTOVEN cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue JANTOVEN before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.

Polycythemia vera Vasculitis Diabetes mellitus 5.8 Endogenous Factors Affecting INR The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).

Advise patients to: Tell their physician if they fall often as this may increase their risk for complications.

Strictly adhere to the prescribed dosage schedule.

Do not take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter drugs, and botanical (herbal) products except on advice of your physician.

Notify their physician immediately if any unusual bleeding or symptoms occur.

Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness.

Contact their doctor –immediately if they think they are pregnant –to discuss pregnancy planning –if they are considering breast-feeding Avoid any activity or sport that may result in traumatic injury.

Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy.

Carry identification stating that they are taking JANTOVEN.

If the prescribed dose of JANTOVEN is missed, take the dose as soon as possible on the same day but do not take a double dose of JANTOVEN the next day to make up for missed doses.

Eat a normal, balanced diet to maintain a consistent intake of vitamin K.

Avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables.

Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever.

Be aware that if therapy with JANTOVEN is discontinued, the anticoagulant effects of JANTOVEN may persist for about 2 to 5 days.

Manufactured by UPSHER-SMITH LABORATORIES, INC.

Maple Grove, MN 55369 Revised 0116

DOSAGE AND ADMINISTRATION

2 Individualize dosing regimen for each patient, and adjust based on INR response.

(2.1, 2.2) Knowledge of genotype can inform initial dose selection.

(2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range.

Obtain subsequent INR determinations every 1 to 4 weeks.

(2.4) Review conversion instructions from other anticoagulants.

(2.8) 2.1 Individualized Dosing The dosage and administration of JANTOVEN must be individualized for each patient according to the patient’s INR response to the drug.

Adjust the dose based on the patient’s INR and the condition being treated.

Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with JANTOVEN [see References (15) ].

2.2 Recommended Target INR Ranges and Durations for Individual Indications An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.

Venous Thromboembolism (including deep venous thrombosis [DVT] and PE) Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations.

The duration of treatment is based on the indication as follows: For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended.

For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months.

After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient.

For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended.

For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.

Atrial Fibrillation In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).

In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.

In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.

For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended.

For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.

Mechanical and Bioprosthetic Heart Valves For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended.

For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended.

For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended.

For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended.

If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.

Post-Myocardial Infarction For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended.

Recurrent Systemic Embolism and Other Indications Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology.

However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

2.3 Initial and Maintenance Dosing The appropriate initial dosing of JANTOVEN varies widely for different patients.

Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by: Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5) ] Select the initial dose based on the expected maintenance dose, taking into account the above factors.

Modify this dose based on consideration of patient-specific clinical factors.

Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ].

Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

Individualize the duration of therapy for each patient.

In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2) ].

Dosing Recommendations without Consideration of Genotype If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of JANTOVEN is usually 2 to 5 mg once daily.

Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated.

Typical maintenance doses are 2 to 10 mg once daily.

Dosing Recommendations with Consideration of Genotype Table 1 displays three ranges of expected maintenance JANTOVEN doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see Clinical Pharmacology (12.5) ].

If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose.

Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.

Table 1: Three Ranges of Expected Maintenance JANTOVEN Daily Doses Based on CYP2C9 and VKORC1 GenotypesRanges are derived from multiple published clinical studies.

VKORC1 –1639G>A (rs9923231) variant is used in this table.

Other co-inherited VKORC1 variants may also be important determinants of warfarin dose.

VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 2.4 Monitoring to Achieve Optimal Anticoagulation JANTOVEN is a narrow therapeutic range (index) drug, and its action may be affected by factors such as other drugs and dietary vitamin K.

Therefore, anticoagulation must be carefully monitored during JANTOVEN therapy.

Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range.

After stabilization, maintain dosing within the therapeutic range by performing periodic INRs.

The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks.

Perform additional INR tests when other warfarin products are interchanged with JANTOVEN, as well as whenever other medications are initiated, discontinued, or taken irregularly.

Heparin, a common concomitant drug, increases the INR [see Dosage and Administration (2.8) and Drug Interactions (7) ].

Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of JANTOVEN therapy.

2.5 Missed Dose The anticoagulant effect of JANTOVEN persists beyond 24 hours.

If a patient misses a dose of JANTOVEN at the intended time of day, the patient should take the dose as soon as possible on the same day.

The patient should not double the dose the next day to make up for a missed dose.

2.7 Treatment During Dentistry and Surgery Some dental or surgical procedures may necessitate the interruption or change in the dose of JANTOVEN therapy.

Consider the benefits and risks when discontinuing JANTOVEN even for a short period of time.

Determine the INR immediately prior to any dental or surgical procedure.

In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of JANTOVEN to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

2.8 Conversion From Other Anticoagulants Heparin Since the full anticoagulant effect of JANTOVEN is not achieved for several days, heparin is preferred for initial rapid anticoagulation.

During initial therapy with JANTOVEN, the interference with heparin anticoagulation is of minimal clinical significance.

Conversion to JANTOVEN may begin concomitantly with heparin therapy or may be delayed 3 to 6 days.

To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap JANTOVEN therapy with heparin for 4 to 5 days and until JANTOVEN has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued.

As heparin may affect the INR, patients receiving both heparin and JANTOVEN should have INR monitoring at least: 5 hours after the last intravenous bolus dose of heparin, or 4 hours after cessation of a continuous intravenous infusion of heparin, or 24 hours after the last subcutaneous heparin injection.

JANTOVEN may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin.

A severe elevation (>50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.

Other Anticoagulants Consult the labeling of other anticoagulants for instructions on conversion to JANTOVEN.

house mouse skin extract 20000 UNT/ML Injectable Solution

Generic Name: CATTLE EPITHELIUM

Brand Name: Cattle Epithelium

Substance Name(s):
BOS TAURUS SKIN

WARNINGS

DO NOT INJECT INTRAVENOUSLY.

Epinephrine 1:1000 should be available.

Concentrated extracts must be diluted with sterile diluent prior to first use on a patient for treatment or intradermal testing.

All concentrates of glycerinated allergenic extracts have the ability to cause serious local and systemic reactions including death in sensitive patients.

Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and /or death.(4) (See Adverse Reactions) An allergenic extract should be temporarily withheld from patients or the dose of the extract adjusted downward if any of the following conditions exist: (1) Severe symptoms of rhinitis and/or asthma (2) Infections or flu accompanied by fever and (3) Exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection.

When switching patients to a new lot of the same extract the initial dose should be reduced 3/4 so that 25% of previous dose is administered.

OVERDOSAGE

Overdose can cause both local and systemic reactions.

An overdose may be prevented by careful observation and questioning of the patient about the previous injection.

If systemic or anaphylactic reaction, does occur, apply a tourniquet above the site of injection and inject intramuscularly or subcutaneously 0.3 to 0.5ml of 1:1000 Epinephrine Hydrochloride into the opposite arm.

The dose may be repeated in 5-10 minutes if necessary.

Loosen the tourniquet at least every 10 minutes.

The Epinephrine Hydrochloride 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 6-12 years it is 0.2 ml.

Patients unresponsive to Epinephrine may be treated with Theophylline.

Studies on asthmatic subjects reveal that plasma concentrations of Theophylline of 5 to 20 µg/ml are associated with therapeutic effects.

Toxicity is particularly apparent at concentrations greater than 20 µg/ml.

A loading dose of Aminophylline of 5.8 mg/kg intravenously followed by 0.9 mg/kg per hour results in plasma concentrations of approximately 10 µg/ml for patients not previously receiving theophylline.

(Mitenko and Ogilive, Nicholoson and Chick,1973) Other beta-adrenergic drugs such as Isoproterenol, Isoetharine, or Albuterol may be used by inhalation.

The usual dose to relieve broncho-constriction in asthma is 0.5 ml of the 0.5% solution for Isoproterenol HCl.

The Albuterol inhaler delivers approximately 90 mcg of Albuterol from the mouthpiece.

The usual dosage for adults and children would be two inhalations repeated every 4-6 hours.

Isoetharine supplied in the Bronkometer unit delivers approximately 340 mcg Isoetharine.

The average dose is one to two inhalations.

Respiratory obstruction not responding to parenteral or inhaled bronchodilators may require oxygen, intubation and the use of life support systems.

DESCRIPTION

Allergenic extracts are sterile solutions consisting of the extractable components from various biological sources including pollens, inhalants, molds, animal epidermals and insects.

Aqueous extracts are prepared using cocas fluid containing NaCl 0.5%, NaHCO3 0.0275%, WFI, preservative 0.4% Phenol.

Glycerinated allergenic extracts are prepared with cocas fluid and glycerin to produce a 50% (v/v) allergenic extract.

Allergenic Extracts are supplied as concentrations designated as protein nitrogen units (PNU) or weight/volume (w/v) ratio.

Standardized extracts are designated in Bioequivalent Allergy Units (BAU) or Allergy Units (AU).

(See product insert for standardized extracts) For diagnostic purposes, allergenic extracts are to be administered by prick-puncture or intradermal routes.

Allergenic extracts are administered subcutaneously for immunotherapy injections.

HOW SUPPLIED

Allergenic extracts are supplied with units listed as: Weight/volume (W/V), Protein Nitrogen Units (PNU/ml), Allergy Units (AU/ml) or Bioequivalent Allergy Units (BAU/ml).

Sizes: Diagnostic Scratch: 5 ml dropper application vials Diagnostic Intradermal: 5 ml or 10 ml vials.

Therapeutic Allergens: 5 ml, 10 ml, 50 ml multiple dose vials.

INDICATIONS AND USAGE

Allergenic extracts are indicated for use in diagnostic testing and as part of a treatment regime for allergic disease, as established by allergy history and skin test reactivity.

Allergenic extracts are indicated for the treatment of allergen specific allergic disease for use as hyposensitization or immunotherapy when avoidance of specific allergens can not be attained.

The use of allergenic extracts for therapeutic purpose has been established by well-controlled clinical studies.

Allergenic extracts may be used as adjunctive therapy along with pharmacotherapy which includes antihistamines, corticosteroids, and cromoglycate, and avoidance measures.

Allergenic extracts for therapeutic use should be given using only the allergen selection to which the patient is allergic, has a history of exposure and are likely to be exposed to again.

BOXED WARNING

WARNING Diagnostic and therapeutic allergenic extracts are intended to be administered by a physician who is an allergy specialist and experienced in allergenic diagnostic testing and immunotherapy and the emergency care of anaphylaxis.

This product should not be injected intravenously.

Deep subcutaneous routes have been safe.

Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and/or death.

(See Adverse Reactions) Serious adverse reactions should be reported to Nelco Laboratories immediately and a report filed to: MedWatch, The FDA Medical Product Problem Reporting Program, at 5600 Fishers Lane, Rockville, Md.

20852-9787, call 1-800-FDA-1088.

Extreme caution should be taken when using allergenic extracts for patients who are taking beta-blocker medications.

In the event of a serious adverse reaction associated with the use of allergenic extracts, patients receiving beta-blockers may not be responsive to epinephrine or inhaled brochodialators.(1) (See Precautions) Allergenic extracts should be used with caution for patients with unstable or steroid-dependent asthma or underlying cardiovascular disease.

(See Contraindications)

DOSAGE AND ADMINISTRATION

General Precautions Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permits.

The dosage of allergenic extracts is dependent upon the purpose of the administration.

Allergenic extracts can be administered for diagnostic use or for therapeutic use.

When allergenic extracts are administered for diagnostic use, the dosage is dependent upon the method used.

Two methods commonly used are scratch testing and intradermal testing.

Both types of tests result in a wheal and flare response at the site of the test which usually develops rapidly and may be read in 20-30 minutes.

Diagnostic Use : Scratch Testing Method Scratch testing is considered a simple and safe method although less sensitive than the intradermal test.

Scratch testing can be used to determine the degree of sensitivity to a suspected allergen before using the intradermal test.

This combination lessens the severity of response to an allergen which can occur in a very sensitive patient.

The most satisfactory testing site is the patient’s back or volar surface of the arms from the axilla to 2.5 or 5cm above the wrist, skipping the anti-cubital space.

If using the back as a testing site, the most satisfactory area 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.

Allergenic extracts for diagnostic use are to be administered in the following manner: To scratch surface of skin, use a circular scarifier.

Do not draw blood.

Tests sites should be 4 cm apart to allow for wheal and flare reaction.

1-30 scratch tests may be done at a time.

A separate sterile scratch instrument is to be used on each patient to prevent transmission of homologous serum hepatitis or other infectious agents from one patient to another.

The recommended usual dosage for Scratch testing is one drop of allergen applied to each scratch site.

Do not let dropper touch skin.

Always apply a control scratch with each test set.

Sterile Diluent (for a negative control) is used in exactly the same way as an active test extract.

Histamine may be used as a positive control.

Scratch or prick test sites should be examined at 15 and 30 minutes.

To prevent excessive absorption, wipe off antigens producing large reactions as soon as the wheal appears.

Record the size of the reaction.

Interpretation of Scratch Test Skin tests are graded in terms of the wheal and erythema response noted at 10 to 20 minutes.

Wheal and erythema size may be recorded by actual measurement as compared with positive and negative controls.

A positive reaction consists of an area of erythema surrounding the scarification that is larger than the control site.

For uniformity in reporting reactions, the following system is recommended.

(6) REACTION SYMBOL CRITERIA Negative – No wheal.

Erythema absent or very slight (not more than 1 mm diameter).

One Plus + Wheal absent or very slight erythema present (not more than 3 mm diameter).

Two Plus ++ Wheal not more than 3mm or erythema not more than 5mm diameter.

Three Plus +++ Wheal between 3mm and 5mm diameter, with erythema.

Possible pseudopodia and itching.

Four Plus ++++ A larger reaction with itching and pain.

Diagnostic Use: Intradermal Skin Testing Method Do not perform intradermal test with allergens which have evoked a 2+ or greater response to a Scratch test.

Clean test area with alcohol, place sites 5 cm apart using separate sterile tuberculin syringe and a 25 gauge needle for each allergen.

Insert needle tip, bevel up, into intracutaneous space.

Avoid injecting into blood vessel, pull back gently on syringe plunger, if blood enters syringe change position of needle.

The recommended dosage and range for intradermal testing is 0.05 ml of not more than 100 pnu/ml or 1:1000 w/v (only if puncture test is negative) of allergenic extract.

Inject slowly until a small bleb is raised.

It is important to make each bleb the same size.

Interpretation of Intradermal Test: The patient’s reaction is graded on the basis of size of wheal and flare as compared to control.

Use 0.05 ml sterile diluent as a negative control to give accurate interpretation.

The tests may be accurately interpreted only when the saline control site has shown a negative response.

Observe patient for at least 30 minutes.

Tests can be read in 15-20 minutes.

Edema, erythema and presence of pseudopods, pain and itching may be observed in 4 plus reactions.

For uniformity in reporting reactions the following system is recommended.

(6) REACTION SYMBOL CRITERIA Negative – No increase in size of bleb since injection.

No erythema.

One Plus + An increase in size of bleb to a wheal not more than 5mm diameter, with associated erythema.

Two Plus ++ Wheal between 5mm and 8mm diameter with erythema.

Three Plus +++ Wheal between 8mm and 12mm diameter with erythema and possible pseudopodia and itching or pain.

Four Plus ++++ Any larger reaction with itch and pain, and possible diffuse blush of the skin surrounding the reaction area.

Therapeutic Use: Recommended dosage & range Check the listed ingredients to verify that it matches the prescription ordered.

When using a prescription set, verify the patient’s name and the ingredients listed with the prescription order.

Assess the patient’s physical and emotional status prior to giving as injection.

Do not give injections to patients who are in acute distress.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Dosage of allergenic extracts is a highly individualized matter and varies according to the degree of sensitivity of the patient, his clinical response and tolerance to the extract administered during the early phases of an injection regimen.

The dosage must be reduced when transferring a patient from non-standardized or modified extract to standardized extract.

Any evidence of a local or generalized reaction requires a reduction in dosage during the initial stages of immunotherapy as well as during maintenance therapy.

After therapeutic injections patients should be observed for at least 20 minutes for reaction symptoms.

SUGGESTED DOSAGE SCHEDULE The following schedule may act as a guide.

This schedule has not been proven to be safe or effective.

Sensitive patients may begin with smaller doses of weaker solutions and the dosage increments can be less.

STRENGTH DOSE VOLUME Vial #1 1 0.05 1:100,000 w/v 2 0.10 10 pnu/ml 3 0.15 1 AU/ml 4 0.20 1 BAU/ml 5 0.30 6 0.40 7 0.50 Vial #2 8 0.05 1:10,000 w/v 9 0.10 100 pnu/ml 10 0.15 10 AU/ml 11 0.20 10 BAU/ml 12 0.30 13 0.40 14 0.50 Vial #3 15 0.05 1:1,000 w/v 16 0.10 1,000 pnu/ml 17 0.15 100 AU/ml 18 0.20 100 BAU/ml 19 0.30 20 0.40 21 0.50 Vial #4 22 0.05 1:100 w/v 23 0.07 10,000 pnu/ml 24 0.10 1,000 AU/ml 25 0.15 1,000 BAU/ml 26 0.20 27 0.25 Maintenance Refill 28 0.25 1:100 w/v 29 0.25 10,000 pnu/ml 30 0.25 1,000 AU/ml 31 0.25 1,000 BAU/ml 32 0.25 subsequent doses 33 0.25 Preparation Instructions: All dilutions may be made using sterile buffered diluent.

The calculation may be based on the following ratio: Volume desired x Concentration desired = Volume needed x Concentration available.

Example 1: If a 1:10 w/v extract is available and it is desired to use a 1:1,000 w/v extract substitute as follows: Vd x Cd = Vn x Ca 10ml x 0.001 = Vn x 0.1 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 1:10 vial and place it into a vial containing 9.90 ml of sterile diluent.

The resulting ratio will be a 10 ml vial of 1:1,000 w/v.

Example 2: If a 10,000 pnu/ml extract is available and it is desired to use a 100 pnu/ml extract substitute as follows: 10ml x 100 = Vn x 10,000 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 10,000 pnu/ml vial and place it into a vial containing 9.90 ml of sterile diluent.

The resulting concentration will be a 10 ml vial of 100 pnu/ml.

Example 3: If a 10,000 AU/ml or BAU/ml extract is available and it is desired to use a 100 AU/ml or BAU/ml extract substitute as follows: Vd x Cd = Vn x Ca 10ml x 100 = Vn x 10,000 0.1 ml = Vn Using a sterile technique, remove 0.10 ml of extract from the 10,000 AU/ml or BAU/ml vial and place it into a vial containing 9.90 ml of sterile diluent.

The resulting concentration will be 10ml vial of 100 AU/ml or BAU/ml.

Intervals between doses: The optimal interval between doses of allergenic extract has not been definitely established.

The amount of allergenic extract is increased at each injection by not more than 50%-100% of the previous amount and the next increment is governed by the response to the last injection.

There are three generally accepted methods of pollen hyposensitizing therapy.

PRESEASONAL Treatment starts each year 6 to 8 weeks before onset of seasonal symptoms.

Maximal dose reached just before symptoms are expected.

Injections discontinued during and following season until next year.

CO-SEASONAL Patient is first treated during season with symptoms.

Low initial doses are employed to prevent worsening of condition.

This is followed by an intensive schedule of therapy (i.e.

injections given 2 to 3 times per week).

Fewer Allergists are resorting to this Co-seasonal therapy because of the availability of more effective, symptomatic medications that allow the patient to go through a season relatively symptom free.

PERENNIAL Initially this is the same as pre seasonal.

The allergen is administered twice weekly or weekly for about 20 injections to achieve the maximum tolerated dose.

Then, maintenance therapy may be administered once a week or less frequently.

Duration of Treatment: The usual duration of treatment has not been established.

A period of two or three years of injection therapy constitutes an average minimum course of treatment.

horse skin extract 20000 UNT/ML Injectable Solution

Generic Name: CATTLE EPITHELIUM

Brand Name: Cattle Epithelium

Substance Name(s):
BOS TAURUS SKIN