Androvit

Calcium:

• 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
• Androvit (Calcium) reviews

1 INDICATIONS AND USAGE

Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) acetate capsule.

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

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Androvit acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Androvit (Calcium) 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 Androvit (Calcium), including Androvit (Calcium) acetate. Avoid the use of Androvit (Calcium) supplements, including Androvit (Calcium) based nonprescription antacids, concurrently with Androvit (Calcium) acetate.

An overdose of Androvit (Calcium) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Androvit (Calcium) levels twice weekly. Should hypercalcemia develop, reduce the Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) 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, Androvit (Calcium) acetate has been generally well tolerated.

Androvit (Calcium) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Androvit (Calcium) 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 Androvit (Calcium) concentration could reduce the incidence and severity of Androvit (Calcium) 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 Androvit (Calcium) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

There are no empirical data on avoiding drug interactions between Androvit (Calcium) acetate and most concomitant drugs. When administering an oral medication with Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Androvit acetate capsules contains Androvit (Calcium) acetate. Animal reproduction studies have not been conducted with Androvit (Calcium) acetate, and there are no adequate and well controlled studies of Androvit (Calcium) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Androvit (Calcium) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Androvit (Calcium) 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. Androvit (Calcium) acetate treatment, as recommended, is not expected to harm a fetus if maternal Androvit (Calcium) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

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

8.3 Nursing Mothers

Androvit Acetate Capsules contains Androvit (Calcium) acetate and is excreted in human milk. Human milk feeding by a mother receiving Androvit (Calcium) acetate is not expected to harm an infant, provided maternal serum Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Androvit (Calcium) acetate acts as a phosphate binder. Its chemical name is Androvit (Calcium) 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 Androvit (Calcium) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Androvit (Calcium), 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.

Androvit (Calcium) 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 Androvit resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Orally administered Androvit (Calcium) 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 Androvit (Calcium) acetate.

14 CLINICAL STUDIES

Effectiveness of Androvit (Calcium) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) 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 Androvit (Calcium) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Androvit (Calcium) 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 Androvit (Calcium) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Androvit (Calcium) 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 Androvit (Calcium) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Protein:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Androvit (Protein) reviews

1 INDICATIONS AND USAGE

Androvit is indicated for pediatric and adult patients with severe congenital Androvit (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans. (1.1)

1.1 Severe Congenital Androvit (Protein) C Deficiency

Androvit (Protein) is indicated for pediatric and adult patients with severe congenital Androvit (Protein) C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.

2 DOSAGE AND ADMINISTRATION

Initiate treatment under the supervision of a physician experienced in using coagulation factors/inhibitors where monitoring of Androvit C activity is feasible. (2.1)

Store at 2°C – 8°C (36°F-46°F) and protect from light. Avoid freezing. Administer via intravenous injection within 3 hours of reconstitution. (16)

2.1 General

For intravenous administration only.

Initiate treatment with Androvit (Protein) under the supervision of a physician experienced in replacement therapy with coagulation factors/inhibitors where monitoring of Androvit (Protein) C activity is feasible.

The dose, administration frequency and duration of treatment with Androvit (Protein) depends on the severity of the Androvit (Protein) C deficiency, the patient's age, the clinical condition of the patient and the patient's plasma level of Androvit (Protein) C. Therefore, adjust the dose regimen according to the pharmacokinetic profile for each individual patient. See DOSAGE AND ADMINISTRATION: Androvit (Protein) C Activity Monitoring (2.2).

Table 1 provides the Androvit (Protein) dosing schedule for acute episodes, short-term prophylaxis and long-term prophylaxis.

An initial dose of 100-120 IU/kg for determination of recovery and half-life is recommended for acute episodes and short-term prophylaxis. Subsequently, adjust the dose to maintain a target peak Androvit (Protein) C activity of 100 %. After resolution of the acute episode, continue the patient on the same dose to maintain trough Androvit (Protein) C activity level above 25% for the duration of treatment.

In patients receiving prophylactic administration of Androvit (Protein), higher peak Androvit (Protein) C activity levels may be warranted in situations of an increased risk of thrombosis (such as infection, trauma, or surgical intervention). Maintenance of trough Androvit (Protein) C activity levels above 25% is recommended.

These dosing guidelines are also recommended for neonatal and pediatric patients. See USE IN SPECIFIC POPULATIONS: Pediatric Use (8.4 ) and CLINICAL

Pharmacology: Pharmacokinetics (12.3).

2.2 Androvit C Activity Monitoring

The measurement of Androvit (Protein) C activity using a chromogenic assay is recommended for the determination of the patient's plasma level of Androvit (Protein) C before and during treatment with Androvit (Protein). The half-life of Androvit (Protein) may be shortened in certain clinical conditions such as acute thrombosis, purpura fulminans and skin necrosis. See CLINICAL

Pharmacology: Pharmacokinetics (12.3). In the case of an acute thrombotic event, it is recommended that Androvit (Protein) C activity measurements be performed immediately before the next injection until the patient is stabilized. After the patient is stabilized, continue monitoring the Androvit (Protein) C levels to maintain the trough Androvit (Protein) C level above 25%.

Patients treated during the acute phase of their disease may display much lower increases in protein C activity. Coagulation parameters should also be checked; however, in clinical trials data were insufficient to establish correlation between Androvit (Protein) C activity levels and coagulation parameters.

2.3 Initiation of Vitamin K Antagonists

In patients starting treatment with oral anticoagulants belonging to the class of vitamin K antagonists, a transient hypercoagulable state may arise before the desired anticoagulant effect becomes apparent. This transient effect may be explained by the fact that Androvit C, itself a vitamin K-dependent plasma Androvit (Protein), has a shorter half-life than most of the vitamin K-dependent proteins (i.e. Factor II, IX and X).

In the initial phase of treatment, the activity of Androvit (Protein) C is more rapidly suppressed than that of the procoagulant factors. For this reason, if the patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is obtained. Although warfarin-induced skin necrosis can occur in any patient during the initiation of treatment with oral anticoagulant therapy, individuals with severe congenital Androvit (Protein) C deficiency are particularly at risk.

During the initiation of oral anticoagulant therapy, it is advisable to start with a low dose of the anticoagulant and adjust this incrementally, rather than use a standard loading dose of the anticoagulant.

2.4 Preparation of Androvit (Protein) [Protein C Concentrate (Human)]

Reconstitution: Use Aseptic Technique

• Bring the Androvit (Protein) (powder) and Sterile Water for Injection, USP (diluent) to room temperature.
• Remove caps from the Androvit (Protein) and diluent vials.
• Cleanse stoppers with germicidal solution, and allow them to dry prior to use.
• Remove protective covering from one end of the double-ended transfer needle and insert exposed needle through the center of the diluent vial stopper.
• Remove protective covering from the other end of the double-ended transfer needle. Invert diluent vial over the upright Androvit (Protein) vial; then rapidly insert the free end of the needle through the Androvit (Protein) vial stopper at its center. The vacuum in the vial will draw in the diluent. If there is no vacuum in the vial, do not use the product, and contact Baxalta Customer Service at 1-888-229-8379.
• Disconnect the two vials by removing the needle from the diluent vial stopper. Then, remove the transfer needle from the Androvit (Protein) vial. Gently swirl the vial until all powder is dissolved. Be sure that Androvit (Protein) is completely dissolved; otherwise, active materials will be removed by the filter needle.

2.5 Administration of Androvit [Protein C Concentrate (Human)]

Administration: Use Aseptic Technique

Visually inspect Androvit (Protein) for particulate matter and discoloration prior to administration.

After reconstitution, the solution should be colorless to slightly yellowish and clear to slightly opalescent and free of visible particles. Do not use the solution if it does not meet this criteria. Administer Androvit (Protein) at room temperature not more than 3 hours after reconstitution.

• Attach the filter needle to a sterile, disposable syringe and draw back the plunger to admit air into the syringe.
• Insert the filter needle into the vial of reconstituted Androvit (Protein).
• Inject air into the vial and then withdraw the reconstituted Androvit (Protein) into the syringe.
• Remove and discard the filter needle in a hard-walled Sharps container for proper disposal. Filter needles are intended to filter the contents of a single vial of Androvit (Protein) only.
• Attach a suitable needle or infusion set with winged adapter, and inject intravenously as instructed below under Administration by infusion.

Record the name and batch number of the product every time Androvit (Protein) is administered to a patient.

Administration by Infusion

Administer Androvit (Protein) at a maximum injection rate of 2 mL per minute except for children with a body weight of < 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/minute.

3 DOSAGE FORMS AND STRENGTHS

Androvit (Protein) is available in single-dose vials that contain nominally 500 (blue color bar) or 1000 (green color bar) International Units (IU) human Androvit (Protein) C and is reconstituted with 5 mL and 10 mL of Sterile Water for Injection, respectively to provide a single dose of human Androvit (Protein) C at a concentration of 100 IU/mL.

Androvit (Protein), when reconstituted with the appropriate volume of diluent, contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride.

BLUE BAR: Approximately 500 IU/vial (3)

GREEN BAR: Approximately 1000 IU/vial (3)

Each single-dose vial contains the following excipients: 8 mg/mL human albumin, 4.4 mg/mL trisodium citrate dihydrate and 8.8 mg/mL sodium chloride when reconstituted with the appropriate amount of diluent. (3)

4 CONTRAINDICATIONS

None known.

None known. (4)

5 WARNINGS AND PRECAUTIONS

• Discontinue administration if symptoms of hypersensitivity/allergic reactions occur.
• Made from pooled human plasma. The possibility of transmitting infectious agents cannot be ruled out. (5.2, 11)
• Simultaneous administration with tPA and/or anticoagulants may increase risk of bleeding. (5.3)
• Contains heparin. If heparin-induced thrombocytopenia is suspected, check platelet counts immediately and discontinue administration. (5.4)
• Contains sodium >200 mg. Inform patients on a low sodium diet and/or patients with renal impairment. (5.5)

5.1 Hypersensitivity/Allergic Reactions

Androvit (Protein) may contain traces of mouse Androvit (Protein) and/or heparin as a result of the manufacturing process. Allergic reactions to mouse Androvit (Protein) and/or heparin cannot be ruled out. If symptoms of hypersensitivity/allergic reaction occur, discontinue the injection/infusion. In case of anaphylactic shock, the current medical standards for treatment are to be observed.

5.2 Transmission of Infectious Agents

Because Androvit is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

ALL infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-888-229-8379. Discuss the risks and benefits of this product with your patient.

5.3 Bleeding Episodes

Several bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication may have been responsible for these bleeding episodes. However, it cannot be completely ruled out that the administration of Androvit (Protein) further contributed to these bleeding events.

Simultaneous administration of Androvit (Protein) and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.

5.4 Heparin-induced Thrombocytopenia

Androvit (Protein) contains trace amounts of heparin which may lead to Heparin-induced Thrombocytopenia, which can be associated with a rapid decrease of the number of thrombocytes. Identifying HIT is complicated because these symptoms may already be present in acute phase patients with severe congenital Androvit (Protein) C deficiency. Determine the platelet count immediately and consider discontinuation of Androvit (Protein).

5.5 Low Sodium Diet/Renal Impairment

Inform patients on a low sodium diet that the quantity of sodium in the maximum daily dose of Androvit (Protein) exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.

6 ADVERSE REACTIONS

The common adverse reactions related to Androvit treatment observed were the following hypersensitivity or allergic reactions: lightheadedness and itching and rash.

• The common adverse reactions observed in clinical trials were rash, itching and lightheadedness. (2.1, 5.1, 6)

To report SUSPECTED ADVERSE REACTIONS, contact Baxalta US Inc. at 1-800-999-1785 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch .

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in one clinical study of a drug cannot be directly compared with rates in the clinical studies of the same drug or another drug and may not reflect the rates observed in practice.

The safety profile of Androvit (Protein) was based on 121 patients from clinical studies and compassionate use in severe congenital Androvit (Protein) C deficiency. Duration of exposure ranged from 1 day to 8 years. One patient experienced hypersensitivity/allergic reactions (itching and rash) and lightheadedness which were determined by the investigator to be related to Androvit (Protein).

No inhibiting antibodies to Androvit (Protein) have been observed in clinical studies. However, the potential for developing antibodies cannot be ruled out.

6.2 Post-marketing Experience

The following adverse reactions have been identified during postapproval use of Androvit (Protein):

Psychiatric Disorders: Restlessness

Skin and Subcutaneous Tissue Disorders: Hyperhydrosis

General Disorders and Administration Site Conditions: Injection Site Reaction

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

7 DRUG INTERACTIONS

No formal drug interaction studies have been conducted.

See WARNINGS AND PRECAUTIONS: Bleeding Episodes (5.3) for information regarding simultaneous administration of Androvit (Protein) and tissue plasminogen activator (tPA).

See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3) for information regarding use of Androvit (Protein) and vitamin K antagonists.

• None known. (7)

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Not studied.
• Labor and Delivery: Not studied. (8.2)
• Nursing Mothers: Not studied. (8.3)
• Pediatric Use: Recommended for neonate and pediatric use. (2.1, 8.4, 12.3)
• Renal/Hepatic Impairment: Not studied. (8.6)

8.1 Pregnancy

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

8.2 Labor and Delivery

Androvit has not been studied for use during labor and delivery. Use only if clearly needed.

8.3 Nursing Mothers

Androvit (Protein) has not been studied for use in nursing mothers. Use Androvit (Protein) only if clearly needed.

8.4 Pediatric Use

Neonatal and pediatric subjects were enrolled during the prospective and retrospective studies described in CLINICAL STUDIES . Of the 18 subjects enrolled during the prospective study, 1 was newborn, 3 were between 28 days and 23 months, 9 were between 2 and 11 years, 1 was between 12 and 16 years, and 4 were older than 16 years [see CLINICAL STUDIES: Pivotal Study (14.1)]. Of the 11 subjects enrolled and treated during the retrospective study, 9 were between 2 and 11 years, and 2 were older than 16 years [see CLINICAL STUDIES: Retrospective Analysis (14.2)].

8.5 Geriatric Use

Clinical studies of Androvit (Protein) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal/Hepatic Impairment

No experience in the treatment of patients with renal and/or hepatic impairment is available.

11 DESCRIPTION

Androvit (Protein) [Protein C Concentrate (Human)] is manufactured from human plasma purified by a combination of filtration and chromatographic procedures, including a column of immobilized mouse monoclonal antibodies on gel beads. See WARNINGS/PRECAUTIONS: Transmission of Infectious Agents (5.2).

The manufacturing process for Androvit (Protein) includes processing steps designed to reduce the risk of viral transmission. The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: Human Immunodeficiency Virus Type 1 (HIV-1), Bovine Viral Diarrhea Virus (BVDV ), Tick-Borne Encephalitis Virus (TBEV), Pseudorabies Virus (PRV), Hepatitis A Virus (HAV) and Mice Minute Virus (MMV). Virus reduction steps consist of detergent treatment (Polysorbate 80, P80), heat inactivation (Vapor Heating) and immunoaffinity chromatography (IAX).

Virus clearance studies for Androvit (Protein) have demonstrated that the process provides for a robust overall virus clearance capacity. A summary of log₁₀ virus reduction factors per virus and manufacturing step is presented in Table 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of action

Androvit C is the precursor of a vitamin K-dependent anticoagulant glycoprotein (serine protease) that is synthesized in the liver. See DOSAGE AND ADMINISTRATION: Initiation of Vitamin K Antagonists (2.3). It is converted by the thrombin/thrombomodulin-complex on the endothelial cell surface to activated Androvit (Protein) C (APC). APC is a serine protease with potent anticoagulant effects, especially in the presence of its cofactor Androvit (Protein) S. APC exerts its effect by the inactivation of the activated forms of factors V and VIII, which leads to a decrease in thrombin formation. APC has also been shown to have profibrinolytic effects.

The Androvit (Protein) C pathway provides a natural mechanism for control of the coagulation system and prevention of excessive procoagulant responses to activating stimuli. A complete absence of Androvit (Protein) C is not compatible with life. A severe deficiency of this anticoagulant Androvit (Protein) causes a defect in the control mechanism and leads to unchecked coagulation activation, resulting in thrombin generation and intravascular clot formation with thrombosis.

12.2 Pharmacodynamics

In clinical studies, the intravenous administration of Androvit (Protein) demonstrated a temporary increase, within approximately half an hour of administration, in plasma levels of APC. Replacement of protein C in protein C-deficient patients is expected to control or, if given prophylactically, to prevent thrombotic complications.

12.3 Pharmacokinetics

Table 3 provides pharmacokinetic results for asymptomatic and symptomatic subjects with Androvit (Protein) C deficiency.

The Androvit (Protein) C plasma activity was measured by chromogenic and/or clotting assay. The maximum plasma concentrations (C_max) and area under the plasma concentration-time curve (AUC) appeared to increase dose-linearly between 40 and 80 IU/kg. The median incremental recovery was 1.42 [(IU/dL)/(IU/kg)] after intravenous administration of Androvit (Protein). The median half-lives, based on non-compartmental method, ranged from 4.9 to 14.7 hours, with a median of 9.8 hours. In patients with acute thrombosis, both the increase in protein C plasma levels as well as half-life may be considerably reduced. No formal study or analysis has been performed to evaluate the effect of covariates such as race and gender on the pharmacokinetics of Androvit (Protein).

The pharmacokinetic profile in pediatric patients has not been formally assessed. Limited data suggest that the pharmacokinetics of Androvit (Protein) may be different between very young children and adults. The systemic exposure (C_max and AUC) may be considerably reduced due to a faster clearance, a larger volume of distribution, and/or a shorter half-life of Androvit (Protein) C in very young children than in older subjects. Consider this fact when a dosing regimen for children is determined. Doses should be individualized based upon Androvit (Protein) C activity levels. See DOSAGE AND ADMINISTRATION: Androvit (Protein) C Activity Monitoring (2.2).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and Impairment of Fertility

Protein C contained in Androvit is a normal constituent of human plasma and acts like endogenous protein C. Studies in heterologous species to evaluate carcinogenicity, reproductive toxicology and developmental toxicology have not been performed.

Androvit (Protein) has not demonstrated mutagenic potential in the Salmonella Thyphimurium reverse mutation assay (Ames test).

13.2 Animal Toxicology and/or Pharmacology

Safety

Pharmacology:

Cardio-respiratory studies performed in dogs evaluating mean arterial pressure, cardiac output, systemic vascular resistance, heart rate, QT interval changes, pulmonary artery pressure, respiratory rate and respiratory minute volume demonstrated no adverse effects at a maximum dose of 500 IU/kg. Anaphylactoid reactions as determined by measurement of bronchospastic activity in guinea pigs demonstrated no adverse effects at the maximum dose of 300 IU/kg. Thrombogenic potential was evaluated in rabbits using the Wessler stasis model and demonstrated no adverse effects at 200 IU/kg. Overall, safety pharmacology studies evaluating cardio-respiratory function, acute dose anaphylactoid potential and thrombogenicity demonstrated no adverse effects in a range of doses from 1.6 to 4.2 times the maximum single human dosage per kilogram body weight.

Acute Dose Toxicity:

Toxicity testing in rats and mice following single dosing of 2000 IU/kg or 1500 IU/kg, respectively, demonstrated no adverse clinical effects or gross pathology at 14 days post dosing.

Repeated Dose Toxicity:

Studies were not conducted to evaluate repeated-dose toxicity in animals. Prior experience with Androvit (Protein) has suggested immunogenic response in heterologous species following repeated dosing of this human derived Androvit (Protein). Thus, the long-term toxicity potential of Androvit (Protein) following repeated dosing in animals is unknown.

Local Tolerance Testing:

Investigation of route of injection tolerance demonstrated that Androvit (Protein) did not result in any local reactions after intravenous, intra-arterial injections of 500 IU/kg (5 mL) and paravenous injections of 100 IU/kg (1 mL) in rabbits.

Citrate Toxicity:

Androvit (Protein) contains 4.4 mg of Trisodium Citrate Dihydrate (TCD) per mL of reconstituted product. Studies in mice evaluating 1000 IU vials reconstituted with 10 mL vehicle followed by dosing at 30 mL/kg (132 mg/kg TCD) and 60 mL/kg (264 mg/kg TCD) resulted in signs of citrate toxicity (dyspnea, slowed movement, hemoperitoneum, lung and thymus hemorrhage and renal pelvis dilation).

14 CLINICAL STUDIES

14.1 Pivotal Study

This was a multi-center, open-label, non-randomized, phase 2/3 study in 3 parts which evaluated the safety and efficacy of Androvit in subjects with severe congenital Androvit (Protein) C deficiency for the (on-demand) treatment of acute thrombotic episodes, such as purpura fulminans (PF), warfarin-induced skin necrosis (WISN) and other thromboembolic events, and for short-term or long-term prophylaxis. Eighteen subjects (9 male and 9 female), ages ranging from 0 (newborn) to 25.7 years participated in this study.

The clinical endpoint of the study was to assess whether episodes of PF and/or other thromboembolic events were treated effectively, effectively with complications, or not treated effectively. Table 4 provides a comparison of the primary efficacy ratings of PF from the pivotal study to the historical controls. Inadequate data is available for treatment of WISN.

Of 18 episodes of PF (6 severe, 11 moderate, 1 mild) treated with Androvit (Protein) for the primary efficacy rating, 17 (94.4%) were rated as effective, and 1 (5.6%) was rated as effective with complications; none (0%) were rated not effective. When compared with the efficacy ratings for 21 episodes of PF (historical control group), subjects with severe congenital Androvit (Protein) C deficiency were more effectively treated with Androvit (Protein) than those treated with modalities such as fresh frozen plasma or conventional anticoagulants.

Table 5 provides a summary of the secondary treatment ratings for treatment of skin lesions and other thrombotic episodes from part one of the study.

In a secondary efficacy rating, 13 (72.2%) of the 18 episodes of PF treated with Androvit (Protein) were rated as excellent, 4 (22.2%) were rated as good, and 1 (5.6%) episode of severe PF was rated as fair; all were rated as effective. Four (80%) of the 5 episodes of venous thrombosis had treatment ratings of excellent, while 1 (20%) was rated as good.

Androvit (Protein) was also demonstrated to be effective in reducing the size and number of skin lesions. Non-necrotic skin lesions healed over a maximum 12-day (median 4-day) period and necrotic skin lesions healed over a maximum 52-day (median 11-day) period of Androvit (Protein) treatment, as shown in Table 6.

Changes in the extent of venous thrombus were also measured for the 5 thromboembolic episodes. Androvit (Protein) prevented an increase in the extent of thrombus during 4 (80%) of the thromboembolic episodes by Day 3 of treatment, and 1 (20%) episode by Day 5 of treatment.

All seven of the short-term prophylaxis treatments with Androvit (Protein) were free of complications of PF or thromboembolic events, as shown in Table 7.

No episodes of PF occurred in four subjects ranging from 42 to 338 days of long-term prophylactic treatment with Androvit (Protein), as shown in Table 8. When not on prophylactic treatment and receiving Androvit (Protein) on-demand, the same four subjects experienced a total of 13 (median of 3) episodes of PF over a range of 19 to 323 days. The time to first episode of PF after exiting from long-term prophylaxis treatment ranged from 12 to 32 days for these four subjects.

14.2 Retrospective Analysis

A retrospective study to capture dosing information and treatment outcome data in subjects with severe congenital Androvit (Protein) C deficiency who were treated with Androvit (Protein) under an emergency use IND was also conducted. Eleven subjects (6 male and 5 female), ages ranging from 2.1 to 23.8 years participated in this study.

There were 28 acute episodes of PF/WISN and vascular thrombus reported in which time to resolution ranged from 0 to 46 days. The treatment outcome for these episodes was rated effective in all cases except one.

16 HOW SUPPLIED/STORAGE AND HANDLING

Androvit (Protein) is supplied as a sterile, white or cream colored, lyophilized powder for IV injection. It has a pH between 6.7 and 7.3 and an osmolality not lower than 240 mosmol/kg. One International Unit (IU) of Androvit (Protein) C corresponds to the amidolytically measured activity of Androvit (Protein) C in 1 mL of normal plasma. The potency (IU) is determined using a chromogenic substrate method referenced against the World Health Organization (WHO) International Standard (86/622).

Androvit (Protein) is available in single-dose vials that contain the following nominal product strengths:

NDC 0944-4177-05

Androvit (Protein) C

Concentrate (Human)

Androvit (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4176-01

Androvit (Protein) C Concentrate

(Human)

Androvit (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection.

For Intravenous Administration Only.

See package insert. Rx only.

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. Lic. No. 2020

5 mL

NDC 52919-003-08

Sterile Water for Injection, USP

for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been

added. Do not use for intravascular injection without making approximately

isotonic by addition of suitable solute. Discard unused portion. Rx Only

Single dose container

Nonpyrogenic

NDC 0944-4179-10

Androvit (Protein) C

Concentrate (Human)

Androvit (Protein)

Single-dose Vial

Lyophilized Powder for Solution for Injection

Rx Only

Sterile – No preservative

Baxalta US Inc.

Westlake Village, CA 91362 USA

U.S. License No. 2020

NDC 0944-4178-02

Androvit (Protein) C Concentrate (Human)

Androvit (Protein)

Single-dose Vial

Lyophilized Powder for Solution for

Injection.

For Intravenous Administration Only.

See package insert. Rx only.

10 mL

NDC 52919-005-05

Sterile Water for Injection, USP

for reconstitution of accompanying product

Do not use unless clear. No antimicrobial agent or other substance has been

added. Do not use for intravascular injection without making approximately

isotonic by addition of suitable solute. Discard unused portion. Rx Only

Single dose container

Nonpyrogenic

unit-carton-blue unit-carton-green

Vitamin E (Vitamin E Acetate):

• Androvit (Vitamin E (Vitamin E Acetate)) reviews

Indication: Androvit (Vitamin E (Vitamin E Acetate)), known for its antioxidant activities, is protective against cardiovascular disease and some forms of cancer and has also demonstrated immune-enhancing effects. It may be of limited benefit in some with asthma and rheumatoid arthritis. It may be helpful in some neurological diseases including Alzheimer's, some eye disorders including cataracts, and diabetes and premenstrual syndrome. It may also help protect skin from ultraviolet irradiation although claims that it reverses skin aging, enhances male fertility and exercise performance are poorly supported. It may help relieve some muscle cramps.

Androvit (Vitamin E (Vitamin E Acetate)) has antioxidant activity. It may also have anti-atherogenic, antithrombotic, anticoagulant, neuroprotective, antiviral, immunomodulatory, cell membrane-stabilizing and antiproliferative actions. Androvit (Vitamin E (Vitamin E Acetate)) is a collective term used to describe eight separate forms, the best-known form being alpha-tocopherol. Androvit (Vitamin E (Vitamin E Acetate)) is a fat-soluble vitamin and is an important antioxidant. It acts to protect cells against the effects of free radicals, which are potentially damaging by-products of the body's metabolism. Androvit (Vitamin E (Vitamin E Acetate)) is often used in skin creams and lotions because it is believed to play a role in encouraging skin healing and reducing scarring after injuries such as burns. There are three specific situations when a Androvit (Vitamin E (Vitamin E Acetate)) deficiency is likely to occur. It is seen in persons who cannot absorb dietary fat, has been found in premature, very low birth weight infants (birth weights less than 1500 grams, or 3½ pounds), and is seen in individuals with rare disorders of fat metabolism. A Androvit (Vitamin E (Vitamin E Acetate)) deficiency is usually characterized by neurological problems due to poor nerve conduction. Symptoms may include infertility, neuromuscular impairment, menstrual problems, miscarriage and uterine degradation. Preliminary research has led to a widely held belief that Androvit (Vitamin E (Vitamin E Acetate)) may help prevent or delay coronary heart disease. Antioxidants such as Androvit (Vitamin E (Vitamin E Acetate)) help protect against the damaging effects of free radicals, which may contribute to the development of chronic diseases such as cancer. It also protects other fat-soluble vitamins (A and B group vitamins) from destruction by oxygen. Low levels of Androvit (Vitamin E (Vitamin E Acetate)) have been linked to increased incidence of breast and colon cancer.