S-3 Sanalesca

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S-3 Sanalesca uses

S-3 Sanalesca consists of Arsenic Trioxide, Calcium Iodide, Lobelia Inflata, Magnesium Phosphate Dibasic, Potassium Phosphate Dibasic, Sodium Phosphate Dibasic.

Arsenic Trioxide:


WARNING: APL DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES, AND ELECTROLYTE MONITORING

APL Differentiation Syndrome: Patients with APL treated with S-3 Sanalesca (Arsenic Trioxide) have experienced symptoms similar to a syndrome called the retinoic-acid-Acute Promyelocytic Leukemia (RA-APL) or APL differentiation syndrome, characterized by fever, dyspnea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis. This syndrome can be fatal. High-dose steroids have been administered at the first suspicion of the APL differentiation syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), immediately initiate high-dose steroids (dexamethasone 10 mg intravenously BID), irrespective of the leukocyte count, and continue for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of S-3 Sanalesca (Arsenic Trioxide) therapy during treatment of the APL differentiation syndrome .

Cardiac Conduction Abnormalities: Before initiating therapy, perform a 12-lead ECG, assess serum electrolytes and creatinine, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QT interval. S-3 Sanalesca (Arsenic Trioxide) can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of torsade de pointes, preexisting QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. One patient (also receiving amphotericin B) had torsade de pointes during induction therapy for relapsed APL with S-3 Sanalesca (Arsenic Trioxide) .

WARNING: APL DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES, AND ELECTROLYTE MONITORING

See full prescribing information for complete boxed warning.

  • Patients have experienced symptoms similar to retinoic-acid-Acute Promyelocytic Leukemia or APL differentiation syndrome, which can be fatal. If symptoms occur, initiate high-dose steroids immediately and continue for at least 3 days until symptoms have abated.
  • S-3 Sanalesca (Arsenic Trioxide) can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal.
  • Before initiating therapy, perform a 12-lead ECG, assess serum electrolytes and creatinine, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QT interval.
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1 INDICATIONS AND USAGE

S-3 Sanalesca (Arsenic Trioxide) is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

S-3 Sanalesca (Arsenic Trioxide) is an arsenical indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.

2 DOSAGE AND ADMINISTRATION

  • For induction therapy, administer intravenously at a dose of 0.15 mg/kg daily until bone marrow remission. Do not exceed 60 doses for total induction.
  • Begin consolidation treatment 3 to 6 weeks after completion of induction therapy. Administer intravenously at a dose of 0.15 mg/kg daily for 25 doses over a period up to 5 weeks. (2.1)
  • Delay treatment for severe non-hematologic adverse reactions. (2.2)
  • Dilute prior to use. (2.3)
  • Administer intravenously over 1-2 hours. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed. (2.3)

2.1 Recommended Dosage

Induction Treatment Schedule: Administer S-3 Sanalesca (Arsenic Trioxide) intravenously at a dose of 0.15 mg/kg daily until bone marrow remission. Do not exceed 60 doses for induction.

Consolidation Treatment Schedule: Begin consolidation treatment 3 to 6 weeks after completion of induction therapy. Administer S-3 Sanalesca (Arsenic Trioxide) intravenously at a dose of 0.15 mg/kg daily for 25 doses over a period up to 5 weeks.

2.2 Dose Adjustment for Non-Hematologic Adverse Reactions

If a severe non-hematologic adverse reaction occurs, consider delaying S-3 Sanalesca (Arsenic Trioxide) infusion until the event has resolved (≤ Grade 1).

2.3 Instructions for Preparation and Intravenous Administration

Administration

Administer S-3 Sanalesca (Arsenic Trioxide) intravenously over 1-2 hours. The infusion duration may be extended up to 4 hours if acute vasomotor reactions are observed. A central venous catheter is not required.

The S-3 Sanalesca (Arsenic Trioxide) ampule is single-use and does not contain any preservatives. Unused portions of each ampule should be discarded properly. Do not mix S-3 Sanalesca (Arsenic Trioxide) with other medications.

Reconstitution

Dilute S-3 Sanalesca (Arsenic Trioxide) with 100 to 250 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, using proper aseptic technique, immediately after withdrawal from the ampule. Do not save any unused portions for later administration.

Safe Handling Procedures

S-3 Sanalesca (Arsenic Trioxide) is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

2.4 Stability

After dilution, S-3 Sanalesca (Arsenic Trioxide) is chemically and physically stable when stored for 24 hours at room temperature and 48 hours when refrigerated.

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3 DOSAGE FORMS AND STRENGTHS

S-3 Sanalesca (Arsenic Trioxide) is an injectable solution for intravenous administration supplied as 10 mg /10 mL of S-3 Sanalesca (Arsenic Trioxide) in single-use ampules.

Injectable solution for intravenous administration supplied as 10 mg/10 ml of S-3 Sanalesca (Arsenic Trioxide) in single-use ampules. (3)

4 CONTRAINDICATIONS

S-3 Sanalesca (Arsenic Trioxide) is contraindicated in patients who are hypersensitive to arsenic.

Hypersensitivity to arsenic. (4)

5 WARNINGS AND PRECAUTIONS

  • Cardiac Conduction Abnormalities: During S-3 Sanalesca therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. (5.2)
  • Carcinogenesis: S-3 Sanalesca (Arsenic Trioxide) is a human carcinogen. Monitor patients for the development of second primary malignancies. (5.3)
  • Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (5.4, 8.1, 8.3)
  • Laboratory Tests: Monitor patient’s electrolyte, hematologic and coagulation profiles and obtain ECGs. (5.5)

5.1 APL Differentiation Syndrome

Nine of 40 patients with APL treated with S-3 Sanalesca (Arsenic Trioxide), at a dose of 0.15 mg/kg, experienced the APL differentiation syndrome. High-dose steroids have been administered at the first suspicion of the APL differentiation syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously BID) should be immediately initiated, irrespective of the leukocyte count, and continued for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of S-3 Sanalesca (Arsenic Trioxide) therapy during treatment of the APL differentiation syndrome .

5.2 Cardiac Conduction Abnormalities: Torsade de Pointes, Complete Heart Block, and QT Prolongation

Torsade de pointes and complete heart block have been reported. QT/QTc prolongation can occur. Sixteen of 40 patients had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after S-3 Sanalesca (Arsenic Trioxide) infusion, and then returned towards baseline by the end of 8 weeks after S-3 Sanalesca (Arsenic Trioxide) infusion.

Prior to initiating therapy with S-3 Sanalesca (Arsenic Trioxide), a 12-lead ECG should be performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine should be assessed. Preexisting electrolyte abnormalities should be corrected and, if possible, drugs that are known to prolong the QT interval should be discontinued. If it is not possible to discontinue the interacting drug, perform cardiac monitoring frequently .

Monitor ECG weekly, and more frequently for clinically unstable patients.

For QTc greater than 500 msec, complete corrective measures and reassess the QTc with serial ECGs prior to initiating S-3 Sanalesca (Arsenic Trioxide). During S-3 Sanalesca (Arsenic Trioxide) therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. Reassess patients who reach an absolute QT interval value > 500 msec and immediately correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending S-3 Sanalesca (Arsenic Trioxide) therapy should be considered. There are no data on the effect of S-3 Sanalesca (Arsenic Trioxide) on the QTc interval during the infusion.

The risk may be increased when S-3 Sanalesca (Arsenic Trioxide) is coadministered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B) .

5.3 Carcinogenesis

The active ingredient of S-3 Sanalesca (Arsenic Trioxide), S-3 Sanalesca (Arsenic Trioxide), is a human carcinogen. Monitor patients for the development of second primary malignancies.

5.4 Embryo-Fetal Toxicity

S-3 Sanalesca can cause fetal harm when administered to a pregnant woman. S-3 Sanalesca (Arsenic Trioxide) was embryolethal and teratogenic in rats when administered on gestation day 9 at a dose approximately 10 times the recommended human daily dose on a mg/m² basis. A related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at a dose approximately 5 times the projected human dose on a mg/m² basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m² basis. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with S-3 Sanalesca (Arsenic Trioxide) .

5.5 Laboratory Tests

The patient’s electrolyte and glucose levels, as well as hepatic, renal, hematologic and coagulation profiles should be monitored at least twice weekly, and more frequently for clinically unstable patients during the induction phase and at least weekly during the consolidation phase.

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6 ADVERSE REACTIONS

The following serious adverse reactions have been associated with S-3 Sanalesca in clinical trials and are discussed in greater detail in other sections of the label.

  • APL Differentiation Syndrome [see Warnings and Precautions ( 5.1)]
  • Cardiac Conduction Abnormalities: Torsade de Pointes, Complete Heart Block, and QT Prolongation
  • Carcinogenesis
  • Embryo-Fetal Toxicity
  • Laboratory Tests

The most common adverse reactions in patients with relapsed or refractory APL were leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-483-8279 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 cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety information was available for 52 patients with relapsed or refractory APL who participated in clinical trials of S-3 Sanalesca (Arsenic Trioxide). Forty patients in the Phase 2 study received the recommended dose of 0.15 mg/kg of which 28 completed both induction and consolidation treatment cycles. An additional 12 patients with relapsed or refractory APL received doses generally similar to the recommended dose. Most patients experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse effects have not been observed to be permanent or irreversible nor do they usually require interruption of therapy.

Serious adverse events (SAEs), Grade 3/4 according to version 2 of the NCI Common Toxicity Criteria, were common. Those SAEs attributed to S-3 Sanalesca (Arsenic Trioxide) in the Phase 2 study of 40 patients with refractory or relapsed APL included APL differentiation syndrome (n=3), hyperleukocytosis (n=3), QTc interval ≥ 500 msec (n=16, 1 with torsade de pointes), atrial dysrhythmias (n=2), and hyperglycemia (n=2).

Table 1 describes the adverse events that were observed in patients, between the ages of 5-73 years, treated for APL with S-3 Sanalesca (Arsenic Trioxide) at the recommended dose at a rate of 5% or more. Similar adverse event profiles were seen in the other patient populations who received S-3 Sanalesca (Arsenic Trioxide).

Table 1

Adverse Events (Any Grade) Occurring in ≥ 5% of 40 Patients with APL Who Received

S-3 Sanalesca (Arsenic Trioxide) (arsenic trioxide) Injection at a Dose of 0.15 mg/kg/day


System organ class

Adverse event


All Adverse Events,

Any Grade


Grade 3/4 Events


n


%


n


%


General disorders and administration site conditions


Fatigue


25


63


2


5


Pyrexia (fever)


25


63


2


5


Edema - non-specific


16


40


Rigors


15


38


Chest pain


10


25


2


5


Injection site pain


8


20


Pain - non-specific


6


15


1


3


Injection site erythema


5


13


Injection site edema


4


10


Weakness


4


10


2


5


Hemorrhage


3


8


Weight gain


5


13


Weight loss


3


8


Drug hypersensitivity


2


5


1


3


Gastrointestinal disorders


Nausea


30


75


Anorexia


9


23


Appetite decreased


6


15


Diarrhea


21


53


Vomiting


23


58


Abdominal pain (lower & upper)


23


58


4


10


Sore throat


14


35


Constipation


11


28


1


3


Loose stools


4


10


Dyspepsia


4


10


Oral blistering


3


8


Fecal incontinence


3


8


Gastrointestinal hemorrhage


3


8


Dry mouth


3


8


Abdominal tenderness


3


8


Diarrhea hemorrhagic


3


8


Abdominal distension


3


8


Metabolism and nutrition disorders


Hypokalemia


20


50


5


13


Hypomagnesemia


18


45


5


13


Hyperglycemia


18


45


5


13


ALT increased


8


20


2


5


Hyperkalemia


7


18


2


5


AST increased


5


13


1


3


Hypocalcemia


4


10

  • Hypoglycemia

3


8


Acidosis


2


5


Nervous system disorders


Headache


24


60


1


3


Insomnia


17


43


1


3


Paresthesia


13


33


2


5


Dizziness (excluding vertigo)


9


23

  • Tremor

5


13


Convulsion


3


8


2


5


Somnolence


3


8


Coma


2


5


2


5


Respiratory


Cough


26


65


Dyspnea


21


53


4


10


Epistaxis


10


25


Hypoxia


9


23


4


10


Pleural effusion


8


20


1


3


Post nasal drip


5


13


Wheezing


5


13


Decreased breath sounds


4


10


Crepitations


4


10


Rales


4


10


Hemoptysis


3


8


Tachypnea


3


8


Rhonchi


3


8


Skin & subcutaneous tissue disorders


Dermatitis


17


43


Pruritus


13


33


1


3


Ecchymosis


8


20


Dry skin


6


15


Erythema - non-specific


5


13


Increased sweating


5


13


Facial edema


3


8


Night sweats


3


8


Petechiae


3


8


Hyperpigmentation


3


8


Non-specific skin lesions


3


8


Urticaria


3


8


Local exfoliation


2


5


Eyelid edema


2


5


Cardiac disorders


Tachycardia


22


55


ECG QT corrected interval prolonged

> 500 msec


16


40


Palpitations


4


10


ECG abnormal other than QT interval

prolongation


3


8


Infections and infestations


Sinusitis


8


20


Herpes simplex


5


13


Upper respiratory tract infection


5


13


1


3


Bacterial infection - non-specific


3


8


1


3


Herpes zoster


3


8


Nasopharyngitis


2


5


Oral candidiasis


2


5


Sepsis


2


5


2


5


Musculoskeletal, connective tissue and bone disorders


Arthralgia


13


33


3


8


Myalgia


10


25


2


5


Bone pain


9


23


4


10


Back pain


7


18


1


3


Neck pain


5


13


Pain in limb


5


13


2


5


Hematologic disorders


Leukocytosis


20


50


1


3


Anemia


8


20


2


5


Thrombocytopenia


7


18


5


13


Febrile neutropenia


5


13


3


8


Neutropenia


4


10


4


10


Disseminated intravascular coagulation


3


8


3


8


Lymphadenopathy


3


8


Vascular disorders


Hypotension


10


25


2


5


Flushing


4


10


Hypertension


4


10


Pallor


4


10


Psychiatric disorders


Anxiety


12


30


Depression


8


20


Agitation


2


5


Confusion


2


5


Ocular disorders


Eye irritation


4


10


Blurred vision


4


10


Dry eye


3


8


Painful red eye


2


5


Renal and urinary disorders


Renal failure


3


8


1


3


Renal impairment


3


8


Oliguria


2


5


Incontinence


2


5


Reproductive system disorders


Vaginal hemorrhage


5


13


Intermenstrual bleeding


3


8


Ear disorders


Earache


3


8


Tinnitus


2


5


The following additional adverse events were reported as related to S-3 Sanalesca (Arsenic Trioxide) treatment in 13 pediatric patients (defined as ages 4 through 20): gastrointestinal (dysphagia, mucosal inflammation/stomatitis, oropharyngeal pain, caecitis), metabolic and nutrition disorders (hyponatremia, hypoalbuminemia, hypophosphatemia, and lipase increased), cardiac failure congestive, respiratory (acute respiratory distress syndrome, lung infiltration, pneumonitis, pulmonary edema, respiratory distress, capillary leak syndrome), neuralgia, and enuresis. Pulmonary edema (n=1) and caecitis (n=1) were considered serious reactions.

6.2 Postmarketing Experience

The following reactions have been reported from clinical trials and/or worldwide postmarketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.

Cardiac disorders: ventricular extrasystoles in association with QT prolongation, and ventricular tachycardia in association with QT prolongation.

Nervous system disorders: peripheral neuropathy

Hematologic disorders: pancytopenia

Investigations: gamma-glutamyltransferase increased

Respiratory, thoracic, and mediastinal disorders: A differentiation syndrome, like retinoic acid syndrome, has been reported with the use of S-3 Sanalesca (Arsenic Trioxide) for the treatment of malignancies other than APL .

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7 DRUG INTERACTIONS

Drugs That Can Prolong the QT/QTc Interval Concomitant use of these drugs and S-3 Sanalesca (Arsenic Trioxide) may increase the risk of serious QT/QTc interval prolongation. Discontinue or replace with an alternative drug that does not prolong the QT/QTc interval while patient is using S-3 Sanalesca (Arsenic Trioxide). Monitor ECGs more frequently in patients when it is not feasible to avoid concomitant use.

Drugs That Can Lead to Electrolyte Abnormalities Electrolyte abnormalities increase the risk of serious QT/QTc interval prolongation. Avoid concomitant administration of drugs that can lead to electrolyte abnormalities. Monitor electrolytes more frequently in patients who must receive concomitant use of these drugs and S-3 Sanalesca (Arsenic Trioxide).

8 USE IN SPECIFIC POPULATIONS

  • Lactation: Discontinue breastfeeding.
  • Renal Impairment: Monitor patients with severe renal impairment (creatinine clearance less than 30 mL/min) for toxicity when treated with S-3 Sanalesca (Arsenic Trioxide); dose reduction may be warranted. (8.6)
  • Hepatic Impairment: Monitor patients with severe hepatic impairment (Child-Pugh Class C) for toxicity when treated with S-3 Sanalesca (Arsenic Trioxide). (8.7)

8.1 Pregnancy

Risk Summary

S-3 Sanalesca (Arsenic Trioxide) can cause fetal harm when administered to a pregnant woman. S-3 Sanalesca (Arsenic Trioxide) was embryolethal and teratogenic in rats when administered on gestation day 9 at a dose approximately 10 times the recommended human daily dose on a mg/m² basis [see Data]. A related trivalent arsenic, sodium arsenite, produced teratogenicity when administered during gestation in mice at a dose approximately 5 times the projected human dose on a mg/m² basis and in hamsters at an intravenous dose approximately equivalent to the projected human daily dose on a mg/m² basis. There are no studies in pregnant women using S-3 Sanalesca (Arsenic Trioxide). Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data

Human Data

One patient who became pregnant while receiving S-3 Sanalesca (Arsenic Trioxide) had a miscarriage.

Animal Data

Studies in pregnant mice, rats, hamsters, and primates have shown that inorganic arsenicals cross the placental barrier when given orally or by injection. An increase in resorptions, neural-tube defects, anophthalmia and microphthalmia were observed in rats administered 10 mg/kg of S-3 Sanalesca (Arsenic Trioxide) on gestation day 9 (approximately 10 times the recommended human daily dose on a mg/m² basis). Similar findings occurred in mice administered a 10 mg/kg dose of a related trivalent arsenic, sodium arsenite (approximately 5 times the projected human dose on a mg/m² basis), on gestation days 6, 7, 8 or 9. Intravenous injection of 2 mg/kg sodium arsenite (approximately equivalent to the projected human daily dose on a mg/m² basis) on gestation day 7 (the lowest dose tested) resulted in neural-tube defects in hamsters.

8.2 Lactation

Arsenic is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from S-3 Sanalesca, discontinue breastfeeding during treatment with S-3 Sanalesca (Arsenic Trioxide).

8.3 Females and Males of Reproductive Potential

Contraception

Females

S-3 Sanalesca (Arsenic Trioxide) can cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during and after treatment with S-3 Sanalesca (Arsenic Trioxide).

Males

Males with female sexual partners of reproductive potential should use effective contraception during and after treatment with S-3 Sanalesca (Arsenic Trioxide).

8.4 Pediatric Use

There are limited clinical data on the pediatric use of S-3 Sanalesca. Of 5 patients below the age of 18 years (age range: 5 to 16 years) treated with S-3 Sanalesca (Arsenic Trioxide), at the recommended dose of 0.15 mg/kg/day, 3 achieved a complete response.

In an additional study, the toxicity profile observed in 13 pediatric patients with APL between the ages of 4 and 20 receiving S-3 Sanalesca (Arsenic Trioxide) at 0.15 mg/kg/day was similar to that observed in adult patients [see Adverse Reactions (6.1)]. No children less than 4 years of age were enrolled in the trial due to the rarity of APL in this age group.

8.5 Geriatric Use

Clinical trials of S-3 Sanalesca (Arsenic Trioxide) (arsenic trioxide) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Monitor elderly patients closely, reflecting the greater frequency of decreased hepatic and renal function, concomitant disease or other drug therapy in this population.

8.6 Patients with Renal Impairment

Exposure of S-3 Sanalesca may be higher in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) should be monitored for toxicity when these patients are treated with S-3 Sanalesca (Arsenic Trioxide), and a dose reduction may be warranted.

The use of S-3 Sanalesca (Arsenic Trioxide) in patients on dialysis has not been studied.

8.7 Patients with Hepatic Impairment

Since limited data are available across all hepatic impairment groups, caution is advised in the use of S-3 Sanalesca (Arsenic Trioxide) in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. Monitor patients with severe hepatic impairment (Child-Pugh Class C) who are treated with S-3 Sanalesca (Arsenic Trioxide) for toxicity.

10 OVERDOSAGE

10.1 Manifestations

Manifestations of S-3 Sanalesca (arsenic trioxide) overdosage include convulsions, muscle weakness and confusion.

10.2 Management

If symptoms of S-3 Sanalesca (Arsenic Trioxide) (arsenic trioxide) overdosage develop, the injection should be immediately discontinued and chelation therapy should be considered.

A conventional protocol for acute arsenic intoxication includes dimercaprol administered at a dose of 3 mg/kg intramuscularly every 4 hours until immediate life-threatening toxicity has subsided. Thereafter, penicillamine at a dose of 250 mg orally, up to a maximum frequency of four times per day (≤ 1 g per day), may be given.

11 DESCRIPTION

S-3 Sanalesca (Arsenic Trioxide) is a sterile injectable solution of S-3 Sanalesca (Arsenic Trioxide). The molecular formula of the drug substance in the solid state is As2O3, with a molecular weight of 197.8 and has the following structural formula:

S-3 Sanalesca (Arsenic Trioxide) is available in 10 mL, single-use ampules containing 10 mg of S-3 Sanalesca (Arsenic Trioxide). S-3 Sanalesca (Arsenic Trioxide) is formulated as a sterile, nonpyrogenic, clear solution of S-3 Sanalesca (Arsenic Trioxide) in water for injection using sodium hydroxide and dilute hydrochloric acid to adjust to pH 8. S-3 Sanalesca (Arsenic Trioxide) is preservative-free. S-3 Sanalesca (Arsenic Trioxide), the active ingredient, is present at a concentration of 1.0 mg/mL. Inactive ingredients and their respective approximate concentrations are sodium hydroxide (1.2 mg/mL) and hydrochloric acid, which is used to adjust the pH to 7.5 - 8.5.

structural formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of S-3 Sanalesca is not completely understood. S-3 Sanalesca (Arsenic Trioxide) causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. S-3 Sanalesca (Arsenic Trioxide) also causes damage or degradation of the fusion protein promyelocytic leukemia (PML)-retinoic acid receptor (RAR)-alpha.

12.2 Pharmacodynamics

Cardiac Electrophysiology

A dedicated QTc study was not performed with S-3 Sanalesca (Arsenic Trioxide). However, in a single arm trial of S-3 Sanalesca (Arsenic Trioxide) (0.15 mg/kg daily), 16 of 40 patients (40%) had a QTc interval greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after S-3 Sanalesca (Arsenic Trioxide) infusion, and then returned towards baseline by the end of 8 weeks after S-3 Sanalesca (Arsenic Trioxide) infusion.

12.3 Pharmacokinetics

The inorganic, lyophilized form of S-3 Sanalesca (Arsenic Trioxide), when placed into solution, immediately forms the hydrolysis product arsenious acid (AsIII). AsIII is the pharmacologically active species of S-3 Sanalesca (Arsenic Trioxide). Monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) are the main pentavalent metabolites formed during metabolism, in addition to arsenic acid (AsV) a product of AsIII oxidation. The pharmacokinetics of arsenical species ([AsIII], [AsV], [MMAV], [DMAV]) were determined in 6 APL patients following once daily doses of 0.15 mg/kg for 5 days per week. Over the total single dose range of 7 to 32 mg (administered as 0.15 mg/kg), systemic exposure (AUC) appears to be linear. Peak plasma concentrations of arsenious acid (AsIII), the primary active arsenical species were reached at the end of infusion (2 hours). Plasma concentration of AsIII declined in a biphasic manner with a mean elimination half-life of 10 to 14 hours and is characterized by an initial rapid distribution phase followed by a slower terminal elimination phase. The daily exposure to AsIII (mean AUC0-24) was 194 ng·hr/mL (n=5) on Day 1 of Cycle 1 and 332 ng·hr/mL (n=6) on Day 25 of Cycle 1, which represents an approximate 2-fold accumulation. The primary pentavalent metabolites, MMAV and DMAV, are slow to appear in plasma (approximately 10-24 hours after first administration of S-3 Sanalesca (Arsenic Trioxide)), but, due to their longer half-life, accumulate more upon multiple dosing than does AsIII. The mean estimated terminal elimination half-lives of the metabolites MMAV and DMAV are 32 hours and 72 hours, respectively. Approximate accumulation ranged from 1.4- to 8-fold following multiple dosing as compared to single dose administration. AsV is present in plasma only at relatively low levels.

Distribution

The volume of distribution (Vss) for AsIII is large (mean 562 L, N=10) indicating that AsIII is widely distributed throughout body tissues. Vss is also dependent on body weight and increases as body weight increases.

Metabolism

Much of the AsIII is distributed to the tissues where it is methylated to the less cytotoxic metabolites, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) by methyltransferases primarily in the liver. The metabolism of S-3 Sanalesca (Arsenic Trioxide) also involves oxidation of AsIII to AsV, which may occur in numerous tissues via enzymatic or nonenzymatic processes. AsV is present in plasma only at relatively low levels following administration of S-3 Sanalesca (Arsenic Trioxide).

Excretion

Approximately 15% of the administered S-3 Sanalesca (Arsenic Trioxide) dose is excreted in the urine as unchanged AsIII. The methylated metabolites of AsIII (MMAV, DMAV) are primarily excreted in the urine. The total clearance of AsIII is 49 L/h and the renal clearance is 9 L/h. Clearance is not dependent on body weight or dose administered over the range of 7-32 mg.

Renal Impairment

The effect of renal impairment on the pharmacokinetics of AsIII, AsV, and the pentavalent metabolites MMAV and DMAV was evaluated in 20 patients with advanced malignancies. Patients were classified as having normal renal function (creatinine clearance [CrCl] > 80 mL/min, n=6), mild renal impairment (CrCl 50-80 mL/min, n=5), moderate renal impairment (CrCl 30-49 mL/min, n=6), or severe renal impairment (CrCl < 30 mL/min, n=3). Following twice weekly administration of 0.15 mg/kg over a 2-hour infusion, the mean AUC0-∞ for AsIII was comparable among the normal, mild and moderate renal impairment groups. However, in the severe renal impairment group, the mean AUC0-∞ for AsIII was approximately 48% higher than that in the normal group.

Systemic exposure to MMAV and DMAV tended to be larger in patients with renal impairment; however, the clinical consequences of this increased exposure are not known. AsV plasma levels were generally below the limit of assay quantitation in patients with impaired renal function . The use of S-3 Sanalesca (Arsenic Trioxide) in patients on dialysis has not been studied.

Hepatic Impairment

The effect of pharmacokinetics of AsIII, AsV, and the pentavalent metabolites MMAV and DMAV was evaluated following administration of 0.25-0.50 mg/kg of S-3 Sanalesca (Arsenic Trioxide) in patients with hepatocellular carcinoma. Patients were classified as having normal hepatic function (n=4), mild hepatic impairment (Child-Pugh class A, n=12), moderate hepatic impairment (Child-Pugh class B, n=3), or severe hepatic impairment (Child-Pugh class C, n=1). No clear trend toward an increase in systemic exposure to AsIII, AsV, MMAV or DMAV was observed with decreasing level of hepatic function as assessed by dose-normalized (per mg dose) AUC in the mild and moderate hepatic impairment groups. However, the one patient with severe hepatic impairment had mean dose-normalized AUC0‑24 and Cmax values 40% and 70% higher, respectively, than those patients with normal hepatic function. The mean dose-normalized trough plasma levels for both MMAV and DMAV in this severely hepatically impaired patient were 2.2-fold and 4.7-fold higher, respectively, than those in the patients with normal hepatic function .

Pediatric Patients

Following IV administration of 0.15 mg/kg/day of S-3 Sanalesca (Arsenic Trioxide) in 10 APL patients (median age = 13.5 years, range 4-20 years), the daily exposure to AsIII (mean AUC0-24h) was 317 ng·hr/mL on Day 1 of Cycle 1 [see U se in Specific Populations (8.4)].

Drug Interactions

No formal assessments of pharmacokinetic drug-drug interactions between S-3 Sanalesca (Arsenic Trioxide) and other drugs have been conducted. The methyltransferases responsible for metabolizing S-3 Sanalesca (Arsenic Trioxide) are not members of the cytochrome P450 family of isoenzymes. In vitro incubation of S-3 Sanalesca (Arsenic Trioxide) with human liver microsomes showed no inhibitory activity on substrates of the major cytochrome P450 (CYP) enzymes such as 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11. The pharmacokinetics of drugs that are substrates for these CYP enzymes are not expected to be affected by concomitant treatment with S-3 Sanalesca (Arsenic Trioxide).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with S-3 Sanalesca (Arsenic Trioxide) by intravenous administration .

S-3 Sanalesca (Arsenic Trioxide) and trivalent arsenite salts have not been demonstrated to be mutagenic to bacteria, yeast or mammalian cells. Arsenite salts are clastogenic in vitro (human fibroblast, human lymphocytes, Chinese hamster ovary cells, Chinese hamster V79 lung cells). Trivalent arsenic produced an increase in the incidence of chromosome aberrations and micronuclei in bone marrow cells of mice.

The effect of arsenic on fertility has not been adequately studied.

14 CLINICAL STUDIES

S-3 Sanalesca (Arsenic Trioxide) has been investigated in 40 relapsed or refractory APL patients, previously treated with an anthracycline and a retinoid regimen, in an open-label, single-arm, non-comparative study. Patients received 0.15 mg/kg/day intravenously over 1 to 2 hours until the bone marrow was cleared of leukemic cells or up to a maximum of 60 days. The CR (absence of visible leukemic cells in bone marrow and peripheral recovery of platelets and white blood cells with a confirmatory bone marrow ≥ 30 days later) rate in this population of previously treated patients was 28 of 40 (70%). Among the 22 patients who had relapsed less than one year after treatment with ATRA, there were 18 complete responders (82%). Of the 18 patients receiving S-3 Sanalesca (Arsenic Trioxide) ≥ one year from ATRA treatment, there were 10 complete responders (55%). The median time to bone marrow remission was 44 days and to onset of CR was 53 days. Three of 5 children, 5 years or older, achieved CR. No children less than 5 years old were treated.

Three to six weeks following bone marrow remission, 31 patients received consolidation therapy with S-3 Sanalesca (Arsenic Trioxide), at the same dose, for 25 additional days over a period up to 5 weeks. In follow-up treatment, 18 patients received further S-3 Sanalesca (Arsenic Trioxide) as a maintenance course. Fifteen patients had bone marrow transplants. At last follow-up, 27 of 40 patients were alive with a median follow-up time of 484 days (range 280 to 755) and 23 of 40 patients remained in complete response with a median follow-up time of 483 days (range 280 to 755).

Cytogenetic conversion to no detection of the APL chromosome rearrangement was observed in 24 of 28 (86%) patients who met the response criteria defined above, in 5 of 5 (100%) patients who met some but not all of the response criteria, and 3 of 7 (43%) of patients who did not respond. RT-PCR conversions to no detection of the APL gene rearrangement were demonstrated in 22 of 28 (79%) of patients who met the response criteria, in 3 of 5 (60%) of patients who met some but not all of the response criteria, and in 2 of 7 (29%) of patients who did not respond.

Hyperleukocytosis (≥ 10 x 10³/uL) developed in 20 of the 40 patients treated. A relationship did not exist between baseline WBC counts and development of hyperleukocytosis nor baseline WBC counts and peak WBC counts. Hyperleukocytosis was not treated with additional chemotherapy. WBC counts during consolidation were not as high as during induction treatment.

Responses were seen across all age groups tested, ranging from 6 to 72 years. The ability to achieve a CR was similar for both genders. There were insufficient patients of Black, Hispanic or Asian derivation to estimate relative response rates in these groups, but responses were seen in members of each group.

Another single center study in 12 patients with relapsed or refractory APL, where patients received S-3 Sanalesca (Arsenic Trioxide) (arsenic trioxide) injection doses generally similar to the recommended dose, had similar results with 9 of 12 (75%) patients attaining a CR.

15 REFERENCES

  • “Hazardous Drugs”, OSHA. [Accessed on February 12, 2015 from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

S-3 Sanalesca (arsenic trioxide) injection is supplied as a sterile, clear, colorless solution in 10 mL glass, single-use ampules.

NDC 63459-600-10 10 mg/10 mL (1 mg/mL) ampule in packages of ten ampules.

16.2 Storage and Handling

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

S-3 Sanalesca (Arsenic Trioxide) is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

17 PATIENT COUNSELING INFORMATION

  • APL Differentiation Syndrome

    Advise patients that symptoms of APL differentiation syndrome include fever, sudden weight gain, labored breathing, and accumulation of fluid in the lungs, heart, and chest. This syndrome is managed by immediate treatment with high dose corticosteroids. Advise patients to immediately report any of these symptoms.

  • ECG Abnormalities – QT Prolongation

    Advise patients that S-3 Sanalesca may cause ECG abnormalities, including QT prolongation. QT prolongation is an increase in the time it takes the heart to relax between beats. If extreme, this prolongation has the potential to cause fainting, irregular heart beat, or more serious side effects. Advise patients to immediately report any of these symptoms. Advise patients to provide a complete list of current medications as caution should be taken when S-3 Sanalesca (Arsenic Trioxide) is coadministered with other medications that can cause QT prolongation or lead to electrolyte abnormalities.

  • Other Side Effects

    Advise patients of the expected adverse reactions of S-3 Sanalesca (Arsenic Trioxide). Most patients in clinical trials experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal symptoms (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse reactions have not been observed to be permanent or irreversible, nor do they usually require interruption of therapy. Advise patients to call their physician at the onset of any treatment-related adverse reactions.

  • Embryo-Fetal Toxicity

    Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions 5.4 and Use in Specific Populations 8.1)].

    Advise females and males of reproductive potential to use effective contraception during and after treatment with S-3 Sanalesca (Arsenic Trioxide) [see Use in Specific Populations ( 8.3)].

  • Lactation

    Advise females to discontinue breastfeeding during treatment with S-3 Sanalesca (Arsenic Trioxide) [see Use in Specific Populations ( 8.2)].



Rx only

Distributed by:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

S-3 Sanalesca (Arsenic Trioxide) is a trademark of Cephalon, Inc. or its affiliates.

©2000-2016 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd, or its affiliates.

All rights reserved.

TRI-009

Trisenox® (arsenic trioxide) Injection 1 mg/mL, 10 x 10 mL Ampules Carton, Part 1 of 2

Trisenox® (arsenic trioxide) Injection 1 mg/mL, 10 x 10 mL Ampules Carton Text

  • NDC 63459-600-10 10 x 10 mL ampules

S-3 Sanalesca (Arsenic Trioxide)®

(arsenic trioxide)

injection

10 mg/10 mL (1 mg/mL)

For Intravenous Use Only

Rx only

Trisenox® (arsenic trioxide) Injection 1 mg/mL, 10 x 10 mL Ampules Carton, Part 2 of 2

Calcium Iodide:


1 INDICATIONS AND USAGE

S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) acetate capsule.

- Capsule: 667 mg S-3 Sanalesca (Calcium Iodide) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting S-3 Sanalesca acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide), including S-3 Sanalesca (Calcium Iodide) acetate. Avoid the use of S-3 Sanalesca (Calcium Iodide) supplements, including S-3 Sanalesca (Calcium Iodide) based nonprescription antacids, concurrently with S-3 Sanalesca (Calcium Iodide) acetate.

An overdose of S-3 Sanalesca (Calcium Iodide) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum S-3 Sanalesca (Calcium Iodide) levels twice weekly. Should hypercalcemia develop, reduce the S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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, S-3 Sanalesca (Calcium Iodide) acetate has been generally well tolerated.

S-3 Sanalesca (Calcium Iodide) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of S-3 Sanalesca (Calcium Iodide) 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.


Preferred Term


Total adverse reactions reported for S-3 Sanalesca (Calcium Iodide) acetate

N=167

N (%)


3 month, open label study of S-3 Sanalesca (Calcium Iodide) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid S-3 Sanalesca (Calcium Iodide) acetate

N=69


S-3 Sanalesca (Calcium Iodide) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


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 S-3 Sanalesca (Calcium Iodide) concentration could reduce the incidence and severity of S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

The drug interaction of S-3 Sanalesca acetate is characterized by the potential of S-3 Sanalesca (Calcium Iodide) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). S-3 Sanalesca (Calcium Iodide) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between S-3 Sanalesca (Calcium Iodide) acetate and most concomitant drugs. When administering an oral medication with S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

S-3 Sanalesca acetate capsules contains S-3 Sanalesca (Calcium Iodide) acetate. Animal reproduction studies have not been conducted with S-3 Sanalesca (Calcium Iodide) acetate, and there are no adequate and well controlled studies of S-3 Sanalesca (Calcium Iodide) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with S-3 Sanalesca (Calcium Iodide) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum S-3 Sanalesca (Calcium Iodide) 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. S-3 Sanalesca (Calcium Iodide) acetate treatment, as recommended, is not expected to harm a fetus if maternal S-3 Sanalesca (Calcium Iodide) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of S-3 Sanalesca (Calcium Iodide) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

S-3 Sanalesca Acetate Capsules contains S-3 Sanalesca (Calcium Iodide) acetate and is excreted in human milk. Human milk feeding by a mother receiving S-3 Sanalesca (Calcium Iodide) acetate is not expected to harm an infant, provided maternal serum S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

S-3 Sanalesca (Calcium Iodide) acetate acts as a phosphate binder. Its chemical name is S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) S-3 Sanalesca (Calcium Iodide), 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.

S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

S-3 Sanalesca (Calcium Iodide) acetate, when taken with meals, combines with dietary phosphate to form an insoluble S-3 Sanalesca (Calcium Iodide) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) acetate.

14 CLINICAL STUDIES

Effectiveness of S-3 Sanalesca (Calcium Iodide) acetate in decreasing serum phosphorus has been demonstrated in two studies of the S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum S-3 Sanalesca (Calcium Iodide) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


S-3 Sanalesca (Calcium Iodide) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) acetate is shown in the Table 3.


* ANOVA of S-3 Sanalesca (Calcium Iodide) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


S-3 Sanalesca (Calcium Iodide) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


S-3 Sanalesca (Calcium Iodide) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with S-3 Sanalesca (Calcium Iodide) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum S-3 Sanalesca (Calcium Iodide) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of S-3 Sanalesca (Calcium Iodide) 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 S-3 Sanalesca (Calcium Iodide) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

S-3 Sanalesca pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


S-3 Sanalesca available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


S-3 Sanalesca destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


S-3 Sanalesca Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


S-3 Sanalesca pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."TRISENOX (ARSENIC TRIOXIDE) INJECTION, SOLUTION [CEPHALON, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."CALCIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Calcium". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming S-3 Sanalesca?

Depending on the reaction of the S-3 Sanalesca after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider S-3 Sanalesca not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is S-3 Sanalesca addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on S-3 Sanalesca, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of S-3 Sanalesca consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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