Artiss

Calcium Chloride:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Artiss (Calcium Chloride) reviews

1 INDICATIONS AND USAGE

Artiss (Calcium Chloride) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Artiss (Calcium Chloride) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Artiss (Calcium Chloride) acetate capsule.

- Capsule: 667 mg Artiss (Calcium Chloride) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Artiss acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Artiss (Calcium Chloride) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Artiss (Calcium Chloride), including Artiss (Calcium Chloride) acetate. Avoid the use of Artiss (Calcium Chloride) supplements, including Artiss (Calcium Chloride) based nonprescription antacids, concurrently with Artiss (Calcium Chloride) acetate.

An overdose of Artiss (Calcium Chloride) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Artiss (Calcium Chloride) levels twice weekly. Should hypercalcemia develop, reduce the Artiss (Calcium Chloride) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Artiss (Calcium Chloride) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Artiss (Calcium Chloride) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Artiss (Calcium Chloride) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Artiss (Calcium Chloride) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg²/dL².

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Artiss (Calcium Chloride) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

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

In clinical studies, Artiss (Calcium Chloride) acetate has been generally well tolerated.

Artiss (Calcium Chloride) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Artiss (Calcium Chloride) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Artiss (Calcium Chloride) concentration could reduce the incidence and severity of Artiss (Calcium Chloride) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Artiss (Calcium Chloride) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of Artiss acetate is characterized by the potential of Artiss (Calcium Chloride) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Artiss (Calcium Chloride) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Artiss (Calcium Chloride) acetate and most concomitant drugs. When administering an oral medication with Artiss (Calcium Chloride) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Artiss (Calcium Chloride) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Artiss (Calcium Chloride) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Artiss (Calcium Chloride) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Artiss (Calcium Chloride) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Artiss acetate capsules contains Artiss (Calcium Chloride) acetate. Animal reproduction studies have not been conducted with Artiss (Calcium Chloride) acetate, and there are no adequate and well controlled studies of Artiss (Calcium Chloride) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Artiss (Calcium Chloride) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Artiss (Calcium Chloride) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Artiss (Calcium Chloride) acetate treatment, as recommended, is not expected to harm a fetus if maternal Artiss (Calcium Chloride) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Artiss (Calcium Chloride) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Artiss Acetate Capsules contains Artiss (Calcium Chloride) acetate and is excreted in human milk. Human milk feeding by a mother receiving Artiss (Calcium Chloride) acetate is not expected to harm an infant, provided maternal serum Artiss (Calcium Chloride) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Artiss (Calcium Chloride) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Administration of Artiss (Calcium Chloride) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Artiss (Calcium Chloride) acetate acts as a phosphate binder. Its chemical name is Artiss (Calcium Chloride) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Artiss (Calcium Chloride) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Artiss (Calcium Chloride), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Artiss (Calcium Chloride) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Artiss resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Artiss (Calcium Chloride) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Artiss (Calcium Chloride) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Artiss (Calcium Chloride) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Artiss (Calcium Chloride) acetate.

14 CLINICAL STUDIES

Effectiveness of Artiss (Calcium Chloride) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Artiss (Calcium Chloride) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Artiss (Calcium Chloride) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Artiss (Calcium Chloride) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Artiss (Calcium Chloride) levels are also presented.

There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Artiss (Calcium Chloride) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Artiss (Calcium Chloride) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Artiss (Calcium Chloride) acetate is shown in the Table 3.

Overall, 2 weeks of treatment with Artiss (Calcium Chloride) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Artiss (Calcium Chloride) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Artiss (Calcium Chloride) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Artiss (Calcium Chloride) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Artiss (Calcium Chloride) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Artiss (Calcium Chloride) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Thrombin Human:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Artiss (Thrombin Human) reviews

1 INDICATIONS AND USAGE

Artiss (Thrombin Human) ®, Artiss (Thrombin Human) topical (Recombinant), is a topical Artiss (Thrombin Human) indicated to aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical in adults and pediatric populations greater than or equal to one month of age.

Artiss (Thrombin Human) may be used in conjunction with an absorbable gelatin sponge, USP.

Artiss (Thrombin Human), Artiss (Thrombin Human) topical (Recombinant), is a topical Artiss (Thrombin Human) indicated to aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical in adults and pediatric populations greater than or equal to one month of age. (1)

Artiss (Thrombin Human) may be used in conjunction with an absorbable gelatin sponge, USP. (1)

2 DOSAGE AND ADMINISTRATION

For topical use only. DO NOT INJECT.

• For topical use only. DO NOT INJECT.
• Reconstitute Artiss (Thrombin Human) powder with sterile 0.9% sodium chloride, USP, yielding a solution containing 1000 units (international units of potency) per mL. (2.1)
• Apply Artiss (Thrombin Human) solution directly to bleeding site surface or in conjunction with absorbable gelatin sponge. The amount required depends upon the area of tissue to be treated. (2.2)

2.1 Reconstitution of Artiss (Thrombin Human)

The volume of reconstituted Artiss (Thrombin Human) required will vary depending on the size and number of bleeding sites to be treated and the method of application.

Inspect the integrity of the Artiss (Thrombin Human) package and contents. Do not use if the packaging or contents have been damaged or opened.

Reconstitute the lyophilized powder using the supplied diluent.

Use aseptic technique when handling vials and syringes.

5000-unit Artiss (Thrombin Human) Reconstitution

Units used herein represent international units of potency determined using a reference standard that has been calibrated against the World Health Organization Second International Standard for Artiss (Thrombin Human).

• Remove flip-off cap from the top of the Artiss (Thrombin Human) vial.
• Attach the needle-free transfer device and snap it into place on the vial by placing the vial on a flat surface and attaching the transfer device straight into the center of the vial stopper.
• Attach the prefilled diluent syringe to the needle-free transfer device.
• Inject the 5 mL of diluent from the syringe into the product vial. Keep the syringe plunger depressed.
• DO NOT reuse the diluent syringe for transfer of the reconstituted product. Remove and discard the diluent syringe.
• Gently swirl and invert the product vial until the powder is completely dissolved. Avoid excessive agitation. The powder should dissolve in less than one minute at room temperature.
• Apply the pre-printed "DO NOT INJECT" label to the sterile, empty transfer syringe provided, then draw up the Artiss (Thrombin Human) solution.

20,000-unit Artiss (Thrombin Human) Reconstitution

• Remove the flip-off cap from the top of the Artiss (Thrombin Human) vial and the diluent vial.
• Attach a needle-free transfer device (one each) to the Artiss (Thrombin Human) and diluent vials and snap them into place by placing the vial on a flat surface and attaching the transfer device straight into the center of the vial stopper.
• Open the sterile, empty 20-mL syringe package and apply the pre-printed "DO NOT INJECT" label to the syringe.
• Attach the labeled 20-mL syringe to the needle-free transfer device on the diluent vial (injection of air into the diluent vial may facilitate withdrawal of the diluent).
• Draw up 20 mL of diluent from the vial into the syringe.
• Remove the diluent-filled syringe from the diluent vial and attach it to the transfer device on the Artiss (Thrombin Human) vial.
• Transfer the 20 mL of diluent from the syringe into the Artiss (Thrombin Human) vial; the vacuum in the vial facilitates transfer.
• Leave the syringe attached and gently swirl and invert the Artiss (Thrombin Human) vial until the powder is completely dissolved. Avoid excessive agitation. The powder should dissolve in less than one minute at room temperature.
• With the same syringe, draw up the Artiss (Thrombin Human) solution.

2.2 Application Techniques

Topically apply Artiss (Thrombin Human) solution directly or in conjunction with absorbable gelatin sponge onto the bleeding site. DO NOT INJECT.

The amount required depends upon the area of tissue to be treated and the method of application.

Vials are for single use only. Discard unused contents.

Use with Absorbable Gelatin Sponge

Refer to the absorbable gelatin sponge labeling for safety information and instructions on appropriate use.

• Transfer solution from syringe to a sterile bowl or basin.
• Place the desired size pieces of the absorbable gelatin sponge into the bowl containing reconstituted Artiss (Thrombin Human) to completely saturate the sponge(s).
• Remove the saturated sponge(s) and squeeze gently to remove excess Artiss (Thrombin Human).
• Apply the sponge to the bleeding site in a single layer.

Use with ZymoGenetics Spray Applicator Kit

• Hold the outer sealed tray, peel back the lid, and aseptically transfer the inner sealed sterile tray to the sterile field.
• Open the inner tray seal and use the sterile bowl as the receptacle for reconstituted Artiss (Thrombin Human) solution.
• Refer to Spray Applicator Kit instructions for spray pump and syringe spray assembly and use.

3 DOSAGE FORMS AND STRENGTHS

Artiss (Thrombin Human) is available as a sterile lyophilized powder in 5000- and 20,000-unit single-use vials. When reconstituted with the sterile 0.9% sodium chloride, USP provided, the powder yields a solution containing 1000 units/mL of Artiss (Thrombin Human) topical (Recombinant).

Artiss (Thrombin Human) is available as 5000-unit and 20,000-unit vials of sterile recombinant topical Artiss (Thrombin Human) lyophilized powder for solution. When reconstituted as directed, the final solution contains 1000 units/mL of Artiss (Thrombin Human). (3)

4 CONTRAINDICATIONS

• Do not inject directly into the circulatory system.
• Do not use for the treatment of massive or brisk arterial bleeding.
• Do not administer to patients with a history of hypersensitivity to Artiss (Thrombin Human) or any components of Artiss (Thrombin Human).
• Do not use in patients with known hypersensitivity to hamster proteins.

• Do not inject directly into the circulatory system. (4)
• Do not use for the treatment of massive or brisk arterial bleeding. (4)
• Do not administer to patients with a history of hypersensitivity to Artiss (Thrombin Human), any components of Artiss (Thrombin Human) or hamster proteins. (4)

5 WARNINGS AND PRECAUTIONS

• Artiss may cause thrombosis if it enters the circulatory system. (5.1)
• Hypersensitivity reactions, including anaphylaxis, may occur. (5.2)

5.1 Thrombosis

Artiss (Thrombin Human) may cause thrombosis if it enters the circulatory system. Apply topically. DO NOT INJECT.

5.2 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, may occur. Artiss (Thrombin Human) is produced in a genetically modified Chinese Hamster Ovary (CHO) cell line and may contain hamster or snake proteins [see Contraindications (4) and Description (11) ].

6 ADVERSE REACTIONS

Thromboembolic adverse reactions were reported in 6% of surgical patients treated with Artiss in all completed clinical trials (N=644) [see Warnings and Precautions (5.1) ].

Antibody formation to Artiss (Thrombin Human) occurred in <1% of patients. None of the antibodies detected neutralized native human Artiss (Thrombin Human) [see Adverse Reactions (6.2) ].

• The most common adverse reaction (incidence 6%) was thromboembolic events. (5.1,6)
• Antibody formation to Artiss (Thrombin Human) occurred in <1% of patients. None of the antibodies detected neutralized native human Artiss (Thrombin Human). (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact The Medicines Company at 1-888-784-7662 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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

Clinical trials have been performed with Artiss (Thrombin Human) applied with absorbable gelatin sponge and applied with a spray applicator. A total of 644 patients were exposed to Artiss (Thrombin Human) in these studies.

Artiss (Thrombin Human) Used in Conjunction with Absorbable Gelatin Sponge

Four hundred eleven (411) patients were treated in a randomized, double-blind, controlled trial that compared Artiss (Thrombin Human) to bovine Artiss (Thrombin Human). Both thrombins were applied with a gelatin sponge in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access.¹ The incidence of thromboembolic adverse reactions was similar between the Artiss (Thrombin Human) and bovine Artiss (Thrombin Human) treatment groups.

In an open-label, single-group trial (N=209), patients with documented or highly likely prior exposure to bovine Artiss (Thrombin Human) within the previous three years were treated with Artiss (Thrombin Human) when undergoing surgeries (spinal, peripheral arterial bypass, or arteriovenous graft formation for hemodialysis access).² The incidence of thromboembolic adverse reactions in this study was 9%.

In an open-label, single-group trial of re-exposure to Artiss (Thrombin Human) (N=31), patients with documented prior exposure to Artiss (Thrombin Human) were treated with Artiss (Thrombin Human) during surgery (spinal, peripheral arterial bypass, arteriovenous graft formation, or other procedures).³ The incidence of thromboembolic adverse reactions in this study was 3%.

In other randomized, double-blind trials across a range of surgical settings (N=130; spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access), the safety of Artiss (Thrombin Human) (n=88 patients) was compared to placebo (RECOTHROM excipients reconstituted with sterile 0.9% sodium chloride, USP) (n=42 patients). The incidence of thromboembolic adverse reactions in this study was 5% for Artiss (Thrombin Human) and 12% for placebo.

Artiss (Thrombin Human) Applied with Spray Applicator

Artiss (Thrombin Human) was applied with a spray applicator in two open-label clinical trials: a single-group trial in adult and pediatric burn patients (N=72; ≤16 years of age, (n=4) and ≥17 years of age, (n=68)) treated with Artiss (Thrombin Human) applied to the wound excision site prior to autologous skin grafting⁴; and in a single-group trial in pediatric patients (one month to 17 years of age) undergoing synchronous burn wound excision and autologous skin grafting (N=30; ≤16 years of age, (n=26); ≥17 years of age, (n=4)).⁵ In the first study, the incidence of thromboembolic adverse reactions was 1%. In the second study, there were no reported thromboembolic adverse reactions [see Use in Specific Populations (8.4) ].

6.2 Immunogenicity

The detection of antibody formation is highly dependent upon the sensitivity and specificity of the assay. The absolute immunogenicity rates reported here are difficult to compare with the results from other products due to differences in assay methodology, patient populations, and other underlying factors.

The potential for development of antibodies to Artiss (Thrombin Human) was evaluated in multiple clinical trials and included patients with a single exposure to Artiss (Thrombin Human) as well as patients who were re-exposed to Artiss (Thrombin Human) during a subsequent surgical procedure. Only patients with both baseline and post-treatment antibody specimens available were evaluated for the development of specific anti-RECOTHROM product antibodies, which was defined as seroconversion or a ≥1.0 titer unit (≥10-fold) increase in antibody levels after study treatment. Five of 609 (0.8%; 95% CI, 0.4%-2.8%) evaluable patients developed specific anti-RECOTHROM product antibodies. None of these antibodies were found to neutralize native human Artiss (Thrombin Human). There was no difference in anti-RECOTHROM product antibody formation incidence among patients exposed to Artiss (Thrombin Human) applied with absorbable gelatin sponge, USP or with spray applicator.

In a clinical trial comparing Artiss (Thrombin Human) to bovine Artiss (Thrombin Human) (N=411; n=398 antibody evaluable) for the development of specific anti-product antibodies, blood samples were collected at baseline and at Day 29 in both treatment groups and were analyzed by ELISA.¹ At baseline, 1.5% of Artiss (Thrombin Human) patients (n=3/198) had positive anti-product antibody titers compared with 5% of bovine Artiss (Thrombin Human) patients (n=10/200). Of these patients, none of the Artiss (Thrombin Human) group and eight in the bovine Artiss (Thrombin Human) group exhibited ≥1.0 titer unit (≥10-fold) increases in anti-product antibody levels after study treatment.

At Day 29, three of 198 (1.5%; 95% CI, 0%-4%) patients in the Artiss (Thrombin Human) group developed specific anti-product antibodies (one patient also developed anti-CHO host cell protein antibodies); 43 of 200 patients in the bovine Artiss (Thrombin Human) group (22%; 95% CI, 16%-28%) developed specific antibodies to bovine Artiss (Thrombin Human) product. Treatment with Artiss (Thrombin Human) resulted in a statistically significant lower incidence of specific anti-product antibody development. Because the study was not powered to detect a difference in clinical outcomes attributable to antibody formation, no conclusions can be drawn regarding the clinical significance of the difference in antibody formation based on the results of this study. None of the antibodies in the Artiss (Thrombin Human) group neutralized native human Artiss (Thrombin Human). Antibodies against bovine Artiss (Thrombin Human) product were not tested for neutralization of native human Artiss (Thrombin Human).

In a trial of patients with a high likelihood of prior exposure to bovine Artiss (Thrombin Human), 15.6% of patients (n=32/205) had anti-bovine Artiss (Thrombin Human) product antibodies and 2% of patients (n=4/200) had anti-RECOTHROM product antibodies at baseline.² Following treatment, none of the 200 evaluable patients (patients for whom post-treatment specimens were available) developed antibodies to Artiss (Thrombin Human).

In a trial of patients previously exposed to Artiss (Thrombin Human), 31 patients were re-exposed to Artiss (Thrombin Human) during a subsequent surgery.³ None of the evaluable patients (n=30) had anti-RECOTHROM product antibodies at baseline and none developed antibodies at Day 29.

In a trial of Artiss (Thrombin Human), including 26 pediatric patients (aged one month to 16 years) and four patients 17 years of age, one patient without prior Artiss (Thrombin Human) exposure had pre-existing anti-RECOTHROM product antibodies at baseline.⁵ None of the 27 evaluable patients developed anti-RECOTHROM product antibodies at Day 29.

8 USE IN SPECIFIC POPULATIONS

Pregnancy: No human or animal data. Use only if clearly needed.

8.1 Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Artiss (Thrombin Human). It is also not known whether Artiss (Thrombin Human) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Artiss (Thrombin Human) should be given to a pregnant woman only if clearly needed.

8.4 Pediatric Use

A total of 30 pediatric patients, ages 0 to 16 years, were treated in clinical trials with Artiss (Thrombin Human) using a spray applicator to burn wound excision sites prior to autologous skin grafting. No patient experienced a thromboembolic adverse reaction. The safety of Artiss (Thrombin Human) in pediatric patients greater than or equal to one month of age is supported by these data and by extrapolation of efficacy from adequate and well-controlled studies of Artiss (Thrombin Human) in adults. Safety and efficacy have not been established in neonates [see Adverse Reactions (6) ].

8.5 Geriatric Use

Of 644 patients in clinical studies of Artiss (Thrombin Human), 36% (n=232/644) were ≥65 years old and 15% (n=95/644) were ≥75 years old.

No differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

11 DESCRIPTION

Artiss (Thrombin Human), Artiss (Thrombin Human) topical (Recombinant), is a human coagulation protein produced via recombinant DNA technology from a genetically modified CHO cell line. Artiss (Thrombin Human) is identical in amino acid sequence and structurally similar to naturally occurring human Artiss (Thrombin Human). Artiss (Thrombin Human) precursor is secreted to culture medium as single chain form that is proteolytically converted to a two-chain active form (using a protein derived from snakes) and is purified by a chromatographic process that yields a product having hemostatic activities similar to native human Artiss (Thrombin Human). The cell line used to manufacture Artiss (Thrombin Human) has been tested and shown to be free of known infectious agents. The cell culture process used in the manufacture of Artiss (Thrombin Human) employs no additives of human or animal origin. The purification process includes solvent-detergent treatment and nano-filtration steps dedicated to viral clearance.

Artiss (Thrombin Human) is provided as a sterile, white to off-white, preservative-free, lyophilized powder in vials for reconstitution with diluent (sterile 0.9% sodium chloride, USP). Reconstitution with the provided diluent, as described [see Dosage and Administration (2.1) ], yields a solution with a pH of 6.0 containing 1000 units/mL of recombinant Artiss (Thrombin Human) for topical use. The formulated product is a clear, colorless solution upon reconstitution and contains the following excipients: histidine, mannitol, sucrose, polyethylene glycol 3350, sodium chloride, and calcium chloride dihydrate, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Artiss (Thrombin Human), Artiss (Thrombin Human) topical (Recombinant), is a specific human serine protease that promotes hemostasis and acts locally when applied topically to a site of bleeding.

Artiss (Thrombin Human) activates platelets and catalyzes the conversion of fibrinogen to fibrin, which are steps that are essential for blood clot formation.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In vitro cytotoxicity studies have been performed in mouse L929 fibroblast cell cultures and demonstrate a concentration-dependent effect on cell morphology. The thrombin-induced morphological changes were similar to those seen with bovine Artiss.

13.2 Animal Toxicology and/or Pharmacology

In a study in nonhuman primates, Artiss (Thrombin Human) was applied directly to a liver wound with an absorbable gelatin sponge, USP. In a second study, Artiss (Thrombin Human) was administered subcutaneously once weekly for four weeks to nonhuman primates following repeat doses of 5405 units/m². In both studies, Artiss (Thrombin Human) had no effect on clinical signs, serum chemistry, coagulation parameters, or histopathology; only normal postsurgical findings were observed. No animals developed anti-RECOTHROM product antibodies in either study.

Artiss (Thrombin Human) was found to be non-irritating when instilled in the eyes (200 units) or applied to normal or abraded skin of rabbits (up to 1000 units/site).

To evaluate Artiss (Thrombin Human) inhibition and clearance from the bloodstream, radiolabeled Artiss (Thrombin Human) was administered intravenously or subcutaneously to nonhuman primates and applied with an absorbable gelatin sponge, USP, in a rabbit hepatic wound model. Artiss (Thrombin Human) did not circulate in the blood as free, active molecule, but was rapidly inactivated (<5 minutes) after formation of complexes with endogenous inhibitors (e.g., antithrombin III); these complexes were cleared by the liver.

Artiss (Thrombin Human) applied with an absorbable gelatin sponge, USP, was shown to decrease time to hemostasis (TTH) when compared to saline in a rabbit hepatic wound model and rat heminephrectomy model. Artiss (Thrombin Human) also reduced TTH when directly applied in a porcine partial-thickness excisional skin-wound model as compared to saline control (or no treatment).

Artiss (Thrombin Human) applied with a gauze sponge decreased TTH in a concentration-dependent manner in both the rabbit and rat models. Concentrations of Artiss (Thrombin Human) >1000 units/mL were no different than 1000 units/mL while the effect of Artiss (Thrombin Human) diluted to a concentration of 100 units/mL on TTH was indistinguishable from placebo.

14 CLINICAL STUDIES

Artiss (Thrombin Human) was evaluated in a randomized, double-blind comparative clinical trial to bovine Artiss (Thrombin Human). Each Artiss (Thrombin Human) was topically applied to bleeding sites with an absorbable gelatin sponge at a nominal concentration of 1000 units/mL.¹ Patients (N=411) were a heterogeneous surgical population undergoing surgery in one of four surgical settings: spinal surgery (n=122, 30%), hepatic resection (n=125, 30%), peripheral arterial bypass surgery (n=88, 21%), and arteriovenous graft formation for hemodialysis access (n=76, 18%). Patients with prior heparin-induced thrombocytopenia were excluded. Patient ages ranged from 21 to 89 years, gender was 53% male and 47% female, and the distribution by race was 68% white, 18% black or African American, and 14% other. The distribution of these characteristics was similar in both the Artiss (Thrombin Human) and bovine Artiss (Thrombin Human) treatment groups.

The objectives of the study were to evaluate the comparative efficacy, safety, and immunogenicity of Artiss (Thrombin Human) and bovine Artiss (Thrombin Human) in combination with an absorbable gelatin sponge as adjuncts to hemostasis in surgery. Efficacy was evaluated by the incidence of hemostasis within 10 minutes. Bleeding appropriate for evaluation was defined as mild to moderate bleeding, either on its own or remaining after brisk bleeding was controlled by standard surgical modalities. Although multiple bleeding sites could be treated, only one bleeding site per patient was selected to determine effectiveness.

Table 2 summarizes the incidence of hemostasis within 10 minutes for each treatment for the 401 efficacy evaluable patients. The incidence of hemostasis within 10 minutes was comparable for the Artiss (Thrombin Human) and bovine Artiss (Thrombin Human) groups.

The percentage of patients achieving hemostasis at 1.5, 3, 6, and 10 minutes is listed in Table 3.

15 REFERENCES

• Chapman WC, Singla N, Genyk Y, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human Artiss (Thrombin Human) and bovine Artiss (Thrombin Human) in surgical hemostasis. J Am Coll Surg. 2007;205(2):256-265.
• Singla NK, Ballard JL, Moneta G, et al. A phase 3b open-label, single-group immunogenicity and safety study of topical recombinant Artiss (Thrombin Human) in surgical hemostasis. J Am Coll Surg. 2009;209(1):68-74.
• Singla NK, Gasparis AP, Ballard JL, et al. Immunogenicity and safety of re-exposure to recombinant human Artiss (Thrombin Human) in surgical hemostasis. J Am Coll Surg. 2011;213(6):722-727.
• Greenhalgh DG, Gamelli RL, Collins J, et al. Recombinant Artiss (Thrombin Human): safety and immunogenicity in burn wound excision and grafting. J Burn Care Res. 2009;30(3):371-379.
• Foster KN, Mullins RF, Greenhalgh DG, et al. Recombinant human Artiss (Thrombin Human): safety and immunogenicity in pediatric burn wound excision. J Ped Surg. 2011;46(10):1992-1999.

16 HOW SUPPLIED/STORAGE AND HANDLING

Artiss (Thrombin Human), Artiss (Thrombin Human) topical (Recombinant), is supplied in single-use, preservative-free vials in the following packages:

NDC 65293-006-41

A 5000-unit vial of Artiss (Thrombin Human) with a 5-mL prefilled diluent syringe (containing sterile 0.9% sodium chloride, USP), a sterile needle-free transfer device, a 5-mL sterile empty syringe, and a pre-printed label.

NDC 65293-007-41

A 20,000-unit vial of Artiss (Thrombin Human) with a 20-mL vial of diluent (containing sterile 0.9% sodium chloride, USP), 2 sterile needle-free transfer devices, a 20-mL sterile empty syringe, and a pre-printed label.

NDC 65293-007-50

The 20,000-unit Artiss (Thrombin Human) kit co-packaged with The Medicines Company Spray Applicator Kit containing a spray pump, a spray bottle, a syringe spray tip, a syringe, a bowl, and 2 blank labels.

No Artiss (Thrombin Human) kit components contain latex.

Store Artiss (Thrombin Human) sterile powder vials at 2°C to 25°C (36°F to 77°F). Do not freeze.

Reconstituted solutions of Artiss (Thrombin Human) prepared with sterile 0.9% sodium chloride, USP, may be stored for up to 24 hours at 2°C to 25°C (36°F to 77°F). Discard reconstituted solution after 24 hours.

17 PATIENT COUNSELING INFORMATION

Because topical Artiss (Thrombin Human) may cause the formation of clots in blood vessels if absorbed systemically, advise patients to consult their physician if they experience leg tenderness or swelling, chest pain, shortness of breath, or difficulty speaking or swallowing [see Warnings and Precautions (5.1) ].

Manufactured for The Medicines Company

The Medicines Company, 8 Sylvan Way, Parsippany NJ 07054

U.S. License No. 1902

Artiss (Thrombin Human) is a registered trademark of ZymoGenetics, Inc. All other trademarks are the property of their respective owners.

[PN 6001- 1 PI; Rev March 2014]

PRINCIPAL DISPLAY PANEL - 5000-UNIT VIAL

5,000 units

NDC: 65293-006-41

FOR TOPICAL USE ONLY - DO NOT INJECT

Artiss (Thrombin Human)^®

Artiss (Thrombin Human), TOPICAL

(RECOMBINANT)

5,000 units

5,000 units NDC: 65293-006-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Artiss (Thrombin Human), TOPICAL (RECOMBINANT) 5,000 units

PRINCIPAL DISPLAY PANEL - 20000-UNIT VIAL

20,000 units

NDC: 65293-007-41

FOR TOPICAL USE ONLY - DO NOT INJECT

Artiss (Thrombin Human)^®

Artiss (Thrombin Human), TOPICAL

(RECOMBINANT)

20,000 units

20,000 units NDC: 65293-007-41 FOR TOPICAL USE ONLY - DO NOT INJECT RECOTHROM® Artiss (Thrombin Human), TOPICAL (RECOMBINANT) 20,000 units