Cat Complex

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Cat Complex uses

Cat Complex consists of Arsenic Trioxide, Nitric Acid, Potassium Dichromate, Pulsatilla.

Arsenic Trioxide:


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

APL Differentiation Syndrome: Patients with APL treated with Cat Complex (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 Cat Complex (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. Cat Complex (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 Cat Complex (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.
  • Cat Complex (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

Cat Complex (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.

Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (Arsenic Trioxide) infusion until the event has resolved (≤ Grade 1).

2.3 Instructions for Preparation and Intravenous Administration

Administration

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

Reconstitution

Dilute Cat Complex (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

Cat Complex (Arsenic Trioxide) is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

2.4 Stability

After dilution, Cat Complex (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

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

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

4 CONTRAINDICATIONS

Cat Complex (Arsenic Trioxide) is contraindicated in patients who are hypersensitive to arsenic.

Hypersensitivity to arsenic. (4)

5 WARNINGS AND PRECAUTIONS

  • Cardiac Conduction Abnormalities: During Cat Complex therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. (5.2)
  • Carcinogenesis: Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (Arsenic Trioxide) infusion, and then returned towards baseline by the end of 8 weeks after Cat Complex (Arsenic Trioxide) infusion.

Prior to initiating therapy with Cat Complex (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 Cat Complex (Arsenic Trioxide). During Cat Complex (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 Cat Complex (Arsenic Trioxide) therapy should be considered. There are no data on the effect of Cat Complex (Arsenic Trioxide) on the QTc interval during the infusion.

The risk may be increased when Cat Complex (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 Cat Complex (Arsenic Trioxide), Cat Complex (Arsenic Trioxide), is a human carcinogen. Monitor patients for the development of second primary malignancies.

5.4 Embryo-Fetal Toxicity

Cat Complex can cause fetal harm when administered to a pregnant woman. Cat Complex (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 Cat Complex (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 Cat Complex 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 Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (Arsenic Trioxide).

Table 1

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

Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (Arsenic Trioxide). (8.7)

8.1 Pregnancy

Risk Summary

Cat Complex (Arsenic Trioxide) can cause fetal harm when administered to a pregnant woman. Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex, discontinue breastfeeding during treatment with Cat Complex (Arsenic Trioxide).

8.3 Females and Males of Reproductive Potential

Contraception

Females

Cat Complex (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 Cat Complex (Arsenic Trioxide).

Males

Males with female sexual partners of reproductive potential should use effective contraception during and after treatment with Cat Complex (Arsenic Trioxide).

8.4 Pediatric Use

There are limited clinical data on the pediatric use of Cat Complex. Of 5 patients below the age of 18 years (age range: 5 to 16 years) treated with Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex 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 Cat Complex (Arsenic Trioxide), and a dose reduction may be warranted.

The use of Cat Complex (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 Cat Complex (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 Cat Complex (Arsenic Trioxide) for toxicity.

10 OVERDOSAGE

10.1 Manifestations

Manifestations of Cat Complex (arsenic trioxide) overdosage include convulsions, muscle weakness and confusion.

10.2 Management

If symptoms of Cat Complex (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

Cat Complex (Arsenic Trioxide) is a sterile injectable solution of Cat Complex (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:

Cat Complex (Arsenic Trioxide) is available in 10 mL, single-use ampules containing 10 mg of Cat Complex (Arsenic Trioxide). Cat Complex (Arsenic Trioxide) is formulated as a sterile, nonpyrogenic, clear solution of Cat Complex (Arsenic Trioxide) in water for injection using sodium hydroxide and dilute hydrochloric acid to adjust to pH 8. Cat Complex (Arsenic Trioxide) is preservative-free. Cat Complex (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 Cat Complex is not completely understood. Cat Complex (Arsenic Trioxide) causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Cat Complex (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 Cat Complex (Arsenic Trioxide). However, in a single arm trial of Cat Complex (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 Cat Complex (Arsenic Trioxide) infusion, and then returned towards baseline by the end of 8 weeks after Cat Complex (Arsenic Trioxide) infusion.

12.3 Pharmacokinetics

The inorganic, lyophilized form of Cat Complex (Arsenic Trioxide), when placed into solution, immediately forms the hydrolysis product arsenious acid (AsIII). AsIII is the pharmacologically active species of Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (Arsenic Trioxide).

Excretion

Approximately 15% of the administered Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (Arsenic Trioxide) and other drugs have been conducted. The methyltransferases responsible for metabolizing Cat Complex (Arsenic Trioxide) are not members of the cytochrome P450 family of isoenzymes. In vitro incubation of Cat Complex (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 Cat Complex (Arsenic Trioxide).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with Cat Complex (Arsenic Trioxide) by intravenous administration .

Cat Complex (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

Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (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 Cat Complex (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

Cat Complex (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.

Cat Complex (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 Cat Complex 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 Cat Complex (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 Cat Complex (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 Cat Complex (Arsenic Trioxide) [see Use in Specific Populations ( 8.3)].

  • Lactation

    Advise females to discontinue breastfeeding during treatment with Cat Complex (Arsenic Trioxide) [see Use in Specific Populations ( 8.2)].



Rx only

Distributed by:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Cat Complex (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

Cat Complex (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

Nitric Acid:


1 INDICATIONS AND USAGE

Cat Complex (Nitric Acid) ® is indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents.

Cat Complex (Nitric Acid) is a vasodilator indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents.

2 DOSAGE AND ADMINISTRATION

The recommended dose is 20 ppm, maintained for up to 14 days or until the underlying oxygen desaturation has resolved.

Doses greater than 20 ppm are not recommended (2.1, 5.2)

Administration:

  • Use only with an Cat Complex (Nitric Acid) DSIR ® operated by trained personnel (2.2)
  • Avoid abrupt discontinuation (2.2, 5.1).

2.1 Dosage

Term and near-term neonates with hypoxic respiratory failure

The recommended dose of Cat Complex (Nitric Acid) is 20 ppm. Maintain treatment up to 14 days or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from Cat Complex (Nitric Acid) therapy.

Doses greater than 20 ppm are not recommended .

2.2 Administration

Training in Administration

The user of Cat Complex (Nitric Acid) and Cat Complex (Nitric Acid) Oxide Delivery Systems must satisfactorily complete a comprehensive periodic training program for health care professionals provided by the delivery system and drug manufacturers. Health professional staff that administers Cat Complex (Nitric Acid) oxide therapy have access to supplier-provided 24 hour/365 days per year technical support on the delivery and administration of Cat Complex (Nitric Acid) at 1-877-566-9466.

Cat Complex (Nitric Acid) Oxide Delivery Systems

Cat Complex (Nitric Acid) must be administered using a calibrated Cat Complex (Nitric Acid) DSIR ® Cat Complex (Nitric Acid) Oxide Delivery System. Only validated ventilator systems should be used in conjunction with Cat Complex (Nitric Acid). Consult the Cat Complex (Nitric Acid) Oxide Delivery System label or call 1-877-566-9466/visit Cat Complex (Nitric Acid).com for a current list of validated systems.

Keep available a backup battery power supply and an independent reserve Cat Complex (Nitric Acid) oxide delivery system to address power and system failures.

Monitoring

Measure methemoglobin within 4-8 hours after initiation of treatment with Cat Complex (Nitric Acid) and periodically throughout treatment .

Monitor for PaO2 and inspired NO2 during Cat Complex (Nitric Acid) administration .

Weaning and Discontinuation

Avoid abrupt discontinuation of Cat Complex (Nitric Acid) . To wean Cat Complex (Nitric Acid), downtitrate in several steps, pausing several hours at each step to monitor for hypoxemia.

3 DOSAGE FORMS AND STRENGTHS

Cat Complex (Nitric Acid) (nitric oxide) gas is available in a 800 ppm concentration.

Cat Complex (Nitric Acid) (nitric oxide) is a gas available in a 800 ppm concentration (3).

4 CONTRAINDICATIONS

Cat Complex (Nitric Acid) is contraindicated in neonates dependent on right-to-left shunting of blood.

Neonates dependent on right-to-left shunting of blood (4).

5 WARNINGS AND PRECAUTIONS

Rebound: Abrupt discontinuation of Cat Complex may lead to worsening oxygenation and increasing pulmonary artery pressure (5.1).

Methemoglobinemia: Methemoglobin increases with the dose of Cat Complex (Nitric Acid) oxide; following discontinuation or reduction of Cat Complex (Nitric Acid) oxide, methemoglobin levels return to baseline over a period of hours (5.2).

Elevated NO2 Levels: Monitor NO2 levels (5.3).

Heart Failure: In patients with pre-existing left ventricular dysfunction, Cat Complex (Nitric Acid) may increase pulmonary capillary wedge pressure leading to pulmonary edema (5.4).

5.1 Rebound Pulmonary Hypertension Syndrome following Abrupt Discontinuation

Wean from Cat Complex (Nitric Acid) . Abrupt discontinuation of Cat Complex (Nitric Acid) may lead to worsening oxygenation and increasing pulmonary artery pressure, i.e., Rebound Pulmonary Hypertension Syndrome. Signs and symptoms of Rebound Pulmonary Hypertension Syndrome include hypoxemia, systemic hypotension, bradycardia, and decreased cardiac output. If Rebound Pulmonary Hypertension occurs, reinstate Cat Complex (Nitric Acid) therapy immediately.

5.2 Hypoxemia from Methemoglobinemia

Cat Complex oxide combines with hemoglobin to form methemoglobin, which does not transport oxygen. Methemoglobin levels increase with the dose of Cat Complex (Nitric Acid); it can take 8 hours or more before steady-state methemoglobin levels are attained. Monitor methemoglobin and adjust the dose of Cat Complex (Nitric Acid) to optimize oxygenation.

If methemoglobin levels do not resolve with decrease in dose or discontinuation of Cat Complex (Nitric Acid), additional therapy may be warranted to treat methemoglobinemia.

5.3 Airway Injury from Nitrogen Dioxide

Nitrogen dioxide (NO2) forms in gas mixtures containing NO and O2. Nitrogen dioxide may cause airway inflammation and damage to lung tissues.

If there is an unexpected change in NO2 concentration, or if the NO2 concentration reaches 3 ppm when measured in the breathing circuit, then the delivery system should be assessed in accordance with the Cat Complex (Nitric Acid) Oxide Delivery System O&M Manual troubleshooting section, and the NO2 analyzer should be recalibrated. The dose of Cat Complex (Nitric Acid) and/or FiO2 should be adjusted as appropriate.

5.4 Worsening Heart Failure

Patients with left ventricular dysfunction treated with Cat Complex (Nitric Acid) may experience pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia and cardiac arrest. Discontinue Cat Complex (Nitric Acid) while providing symptomatic care.

6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere in the label;

Hypoxemia

Worsening Heart Failure

The most common adverse reaction is hypotension. (6).

To report SUSPECTED ADVERSE REACTIONS, contact INO Therapeutics at 1-877-566-9466 and http://www.inomax.com/ 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. The adverse reaction information from the clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Controlled studies have included 325 patients on Cat Complex (Nitric Acid) doses of 5 to 80 ppm and 251 patients on placebo. Total mortality in the pooled trials was 11% on placebo and 9% on Cat Complex (Nitric Acid), a result adequate to exclude Cat Complex (Nitric Acid) mortality being more than 40% worse than placebo.

In both the NINOS and CINRGI studies, the duration of hospitalization was similar in Cat Complex (Nitric Acid) and placebo-treated groups.

From all controlled studies, at least 6 months of follow-up is available for 278 patients who received Cat Complex (Nitric Acid) and 212 patients who received placebo. Among these patients, there was no evidence of an adverse effect of treatment on the need for rehospitalization, special medical services, pulmonary disease, or neurological sequelae.

In the NINOS study, treatment groups were similar with respect to the incidence and severity of intracranial hemorrhage, Grade IV hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary hemorrhage, or gastrointestinal hemorrhage.

In CINRGI, the only adverse reaction (>2% higher incidence on Cat Complex (Nitric Acid) than on placebo) was hypotension (14% vs. 11%).

6.2 Post-Marketing Experience

Post marketing reports of accidental exposure to Cat Complex (Nitric Acid) oxide for inhalation in hospital staff has been associated with chest discomfort, dizziness, dry throat, dyspnea, and headache.

7 DRUG INTERACTIONS

Cat Complex oxide donor compounds may increase the risk of developing methemoglobinemia (7).

7.1 Nitric Oxide Donor Agents

Cat Complex (Nitric Acid) oxide donor agents such as prilocaine, sodium nitroprusside and nitroglycerine may increase the risk of developing methemoglobinemia.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Cat Complex. It is not known if Cat Complex (Nitric Acid) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Cat Complex (Nitric Acid) is not indicated for use in adults.

8.3 Nursing Mothers

Cat Complex (Nitric Acid) oxide is not indicated for use in the adult population, including nursing mothers. It is not known whether Cat Complex (Nitric Acid) oxide is excreted in human milk.

8.4 Pediatric Use

The safety and efficacy of Cat Complex oxide for inhalation has been demonstrated in term and near-term neonates with hypoxic respiratory failure associated with evidence of pulmonary hypertension. Additional studies conducted in premature neonates for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of efficacy . No information about its effectiveness in other age populations is available.

8.5 Geriatric Use

Cat Complex (Nitric Acid) oxide is not indicated for use in the adult population.

10 OVERDOSAGE

Overdosage with Cat Complex (Nitric Acid) is manifest by elevations in methemoglobin and pulmonary toxicities associated with inspired NO2. Elevated NO2 may cause acute lung injury. Elevations in methemoglobin reduce the oxygen delivery capacity of the circulation. In clinical studies, NO2 levels >3 ppm or methemoglobin levels >7% were treated by reducing the dose of, or discontinuing, Cat Complex (Nitric Acid).

Methemoglobinemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation.

11 DESCRIPTION

Cat Complex (Nitric Acid) (nitric oxide gas) is a drug administered by inhalation. Cat Complex (Nitric Acid) oxide, the active substance in Cat Complex (Nitric Acid), is a pulmonary vasodilator. Cat Complex (Nitric Acid) is a gaseous blend of Cat Complex (Nitric Acid) oxide and nitrogen (0.08% and 99.92%, respectively for 800 ppm). Cat Complex (Nitric Acid) is supplied in aluminum cylinders as a compressed gas under high pressure (2000 pounds per square inch gauge [psig]).

The structural formula of Cat Complex (Nitric Acid) oxide (NO) is shown below:

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cat Complex oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, Cat Complex (Nitric Acid) oxide selectively dilates the pulmonary vasculature, and because of efficient scavenging by hemoglobin, has minimal effect on the systemic vasculature.

Cat Complex (Nitric Acid) appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.

12.2 Pharmacodynamics

Effects on Pulmonary Vascular Tone in PPHN

Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, Cat Complex (Nitric Acid) improves oxygenation (as indicated by significant increases in PaO2).

12.3 Pharmacokinetics

The pharmacokinetics of Cat Complex (Nitric Acid) oxide has been studied in adults.

Absorption and Distribution

Cat Complex (Nitric Acid) oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. At this level of oxygen saturation, Cat Complex (Nitric Acid) oxide combines predominantly with oxyhemoglobin to produce methemoglobin and nitrate. At low oxygen saturation, Cat Complex (Nitric Acid) oxide can combine with deoxyhemoglobin to transiently form nitrosylhemoglobin, which is converted to nitrogen oxides and methemoglobin upon exposure to oxygen. Within the pulmonary system, Cat Complex (Nitric Acid) oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhemoglobin to produce methemoglobin and nitrate. Thus, the end products of Cat Complex (Nitric Acid) oxide that enter the systemic circulation are predominantly methemoglobin and nitrate.

Metabolism

Methemoglobin disposition has been investigated as a function of time and Cat Complex (Nitric Acid) oxide exposure concentration in neonates with respiratory failure. The methemoglobin (MetHb) concentration-time profiles during the first 12 hours of exposure to 0, 5, 20, and 80 ppm Cat Complex (Nitric Acid) are shown in Figure 1.

Figure 1: Methemoglobin Concentration-Time Profiles Neonates Inhaling 0, 5, 20 or 80 ppm Cat Complex (Nitric Acid)

Methemoglobin concentrations increased during the first 8 hours of Cat Complex (Nitric Acid) oxide exposure. The mean methemoglobin level remained below 1% in the placebo group and in the 5 ppm and 20 ppm Cat Complex (Nitric Acid) groups, but reached approximately 5% in the 80 ppm Cat Complex (Nitric Acid) group. Methemoglobin levels >7% were attained only in patients receiving 80 ppm, where they comprised 35% of the group. The average time to reach peak methemoglobin was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients, but one patient did not exceed 7% until 40 hours.

Figure 1

Elimination

Nitrate has been identified as the predominant Cat Complex (Nitric Acid) oxide metabolite excreted in the urine, accounting for >70% of the Cat Complex (Nitric Acid) oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the recommended dose (20 ppm), in rats for 20 hr/day for up to two years. Higher exposures have not been investigated.

Cat Complex (Nitric Acid) oxide has demonstrated genotoxicity in Salmonella (Ames Test), human lymphocytes, and after in vivo exposure in rats. There are no animal or human studies to evaluate Cat Complex (Nitric Acid) oxide for effects on fertility.

14 CLINICAL STUDIES

14.1 Treatment of Hypoxic Respiratory Failure

The efficacy of Cat Complex (Nitric Acid) has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of etiologies. Inhalation of Cat Complex (Nitric Acid) reduces the oxygenation index (OI= mean airway pressure in cm H2O × fraction of inspired oxygen concentration [FiO2]× 100 divided by systemic arterial concentration in mm Hg [PaO2]) and increases PaO2 .

NINOS Study

The Neonatal Inhaled Cat Complex (Nitric Acid) Oxide Study (NINOS) was a double-blind, randomized, placebo-controlled, multicenter trial in 235 neonates with hypoxic respiratory failure. The objective of the study was to determine whether inhaled Cat Complex (Nitric Acid) oxide would reduce the occurrence of death and/or initiation of extracorporeal membrane oxygenation (ECMO) in a prospectively defined cohort of term or near-term neonates with hypoxic respiratory failure unresponsive to conventional therapy. Hypoxic respiratory failure was caused by meconium aspiration syndrome (MAS; 49%), pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension of the newborn (PPHN; 17%), or respiratory distress syndrome (RDS; 11%). Infants ≤14 days of age (mean, 1.7 days) with a mean PaO2 of 46 mm Hg and a mean oxygenation index (OI) of 43 cm H2O / mm Hg were initially randomized to receive 100% O2 with (n=114) or without (n=121) 20 ppm Cat Complex (Nitric Acid) oxide for up to 14 days. Response to study drug was defined as a change from baseline in PaO2 30 minutes after starting treatment (full response = >20 mm Hg, partial = 10–20 mm Hg, no response = <10 mm Hg). Neonates with a less than full response were evaluated for a response to 80 ppm Cat Complex (Nitric Acid) oxide or control gas. The primary results from the NINOS study are presented in Table 1.

Control

(n=121)

NO

(n=114)

P value
Death or ECMOExtracorporeal membrane oxygenation , Death or need for ECMO was the study's primary end point 77 (64%) 52 (46%) 0.006
Death 20 (17%) 16 (14%) 0.60
ECMO 66 (55%) 44 (39%) 0.014

Although the incidence of death by 120 days of age was similar in both groups (NO, 14%; control, 17%), significantly fewer infants in the Cat Complex (Nitric Acid) oxide group required ECMO compared with controls (39% vs. 55%, p = 0.014). The combined incidence of death and/or initiation of ECMO showed a significant advantage for the Cat Complex (Nitric Acid) oxide treated group (46% vs. 64%, p = 0.006). The Cat Complex (Nitric Acid) oxide group also had significantly greater increases in PaO2 and greater decreases in the OI and the alveolar-arterial oxygen gradient than the control group (p<0.001 for all parameters). Significantly more patients had at least a partial response to the initial administration of study drug in the Cat Complex (Nitric Acid) oxide group (66%) than the control group (26%, p<0.001). Of the 125 infants who did not respond to 20 ppm Cat Complex (Nitric Acid) oxide or control, similar percentages of NO-treated (18%) and control (20%) patients had at least a partial response to 80 ppm Cat Complex (Nitric Acid) oxide for inhalation or control drug, suggesting a lack of additional benefit for the higher dose of Cat Complex (Nitric Acid) oxide. No infant had study drug discontinued for toxicity. Inhaled Cat Complex (Nitric Acid) oxide had no detectable effect on mortality. The adverse events collected in the NINOS trial occurred at similar incidence rates in both treatment groups . Follow-up exams were performed at 18–24 months for the infants enrolled in this trial. In the infants with available follow-up, the two treatment groups were similar with respect to their mental, motor, audiologic, or neurologic evaluations.

CINRGI Study

This study was a double-blind, randomized, placebo-controlled, multicenter trial of 186 term and near-term neonates with pulmonary hypertension and hypoxic respiratory failure. The primary objective of the study was to determine whether Cat Complex (Nitric Acid) would reduce the receipt of ECMO in these patients. Hypoxic respiratory failure was caused by MAS (35%), idiopathic PPHN (30%), pneumonia/sepsis (24%), or RDS (8%). Patients with a mean PaO2 of 54 mm Hg and a mean OI of 44 cm H2O / mm Hg were randomly assigned to receive either 20 ppm Cat Complex (Nitric Acid) (n=97) or nitrogen gas (placebo; n=89) in addition to their ventilatory support. Patients who exhibited a PaO2 >60 mm Hg and a pH < 7.55 were weaned to 5 ppm Cat Complex (Nitric Acid) or placebo. The primary results from the CINRGI study are presented in Table 2.

Placebo Cat Complex (Nitric Acid) P value
ECMOExtracorporeal membrane oxygenation , ECMO was the primary end point of this study 51/89 (57%) 30/97 (31%) <0.001
Death 5/89 (6%) 3/97 (3%) 0.48

Significantly fewer neonates in the Cat Complex (Nitric Acid) group required ECMO compared to the control group (31% vs. 57%, p<0.001). While the number of deaths were similar in both groups (INOmax, 3%; placebo, 6%), the combined incidence of death and/or receipt of ECMO was decreased in the Cat Complex (Nitric Acid) group (33% vs. 58%, p<0.001).

In addition, the Cat Complex (Nitric Acid) group had significantly improved oxygenation as measured by PaO2, OI, and alveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with Cat Complex (Nitric Acid), 2 (2%) were withdrawn from study drug due to methemoglobin levels >4%. The frequency and number of adverse events reported were similar in the two study groups .

In clinical trials, reduction in the need for ECMO has not been demonstrated with the use of inhaled Cat Complex (Nitric Acid) oxide in neonates with congenital diaphragmatic hernia (CDH).

14.2 Ineffective in Adult Respiratory Distress Syndrome

In a randomized, double-blind, parallel, multicenter study, 385 patients with adult respiratory distress syndrome (ARDS) associated with pneumonia (46%), surgery (33%), multiple trauma (26%), aspiration (23%), pulmonary contusion (18%), and other causes, with PaO2/FiO2 <250 mm Hg despite optimal oxygenation and ventilation, received placebo (n=193) or Cat Complex (Nitric Acid) (n=192), 5 ppm, for 4 hours to 28 days or until weaned because of improvements in oxygenation. Despite acute improvements in oxygenation, there was no effect of Cat Complex (Nitric Acid) on the primary endpoint of days alive and off ventilator support. These results were consistent with outcome data from a smaller dose ranging study of Cat Complex (Nitric Acid) oxide (1.25 to 80 ppm). Cat Complex (Nitric Acid) is not indicated for use in ARDS.

14.3 Ineffective in Prevention of Bronchopulmonary Dysplasia

The safety and efficacy of Cat Complex (Nitric Acid) for the prevention of chronic lung disease [bronchopulmonary dysplasia, (BPD)] in neonates ≤ 34 weeks gestational age requiring respiratory support has been studied in four large, multi-center, double-blind, placebo-controlled clinical trials in a total of 2,600 preterm infants. Of these, 1,290 received placebo, and 1,310 received inhaled Cat Complex (Nitric Acid) oxide at doses ranging from 5-20 ppm, for treatment periods of 7-24 days duration. The primary endpoint for these studies was alive and without BPD at 36 weeks postmenstrual age (PMA). The need for supplemental oxygen at 36 weeks PMA served as a surrogate endpoint for the presence of BPD. Overall, efficacy for the prevention of bronchopulmonary dysplasia in preterm infants was not established. There were no meaningful differences between treatment groups with regard to overall deaths, methemoglobin levels, or adverse events commonly observed in premature infants, including intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and retinopathy of prematurity.

The use of Cat Complex (Nitric Acid) for prevention of BPD in preterm neonates ≤ 34 weeks gestational age is not recommended.

16 HOW SUPPLIED/STORAGE AND HANDLING

Cat Complex (Nitric Acid) (nitric oxide) is available in the following sizes:

Size D Portable aluminum cylinders containing 353 liters at STP of Cat Complex (Nitric Acid) oxide gas in 800 ppm concentration in nitrogen (delivered volume 344 liters) (NDC 64693-002-01)
Size 88 Aluminum cylinders containing 1963 liters at STP of Cat Complex (Nitric Acid) oxide gas in 800 ppm concentration in nitrogen (delivered volume 1918 liters) (NDC 64693-002-02)

Store at 25°C (77°F) with excursions permitted between 15–30°C (59–86°F).

All regulations concerning handling of pressure vessels must be followed.

Protect the cylinders from shocks, falls, oxidizing and flammable materials, moisture, and sources of heat or ignition.

Occupational Exposure

The exposure limit set by the Occupational Safety and Health Administration (OSHA) for Cat Complex (Nitric Acid) oxide is 25 ppm, and for NO2 the limit is 5 ppm.

Distributed by

INO Therapeutics LLC

675 McDonnell Blvd.

Hazelwood, MO 63042

USA

© 2015 Mallinckrodt

Rx only

Cat Complex (Nitric Acid)®

Cat Complex (Nitric Acid) oxide

FOR

INHALATION

800 PPM

CAUTION: HIGH PRESSURE GAS. CAN CAUSE RAPID SUFFOCATION WITHOUT WARNING. Use equipment rated

for cylinder pressure. Store and use with adequate ventilation. Secure cylinder in use and storage. Close valve

after each use and when empty. USE IN ACCORDANCE WITH APPROPRIATE SDS.

WARNING: Administration of this gas mixture may be hazardous or contraindicated. For use only by or under

the supervision of a licensed practitioner who is experienced in the use and administration of gas mixtures, and

is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and

with the hazards, contraindications and side effects and the precautions to be taken.

FIRST AID: IF INHALED, remove person to fresh air. If not breathing, give artificial respiration. If breathing is

difficult, give oxygen. Get medical help.

RETURN WITH 25 PSIG.

TO BE REFILLED ONLY BY A PHARMACEUTICAL FACILITY AUTHORIZED BY INO Therapeutics LLC

Manufactured Under Pharmaceutical Current Good Manufacturing Practices (cGMPs).

DO NOT REMOVE THIS PRODUCT LABEL.

Store at 25°C (77°F)

.

Volume 1963 Liters

Mallinckrodt

Pharmaceuticals

Manufactured by:

Mallinckrodt Manufacturing LLC

1060 Allendale Dr.

Port Allen, LA 70767 USA

For Product Inquiry 1-877-KNOW INO

(566-9466)

UN 1956

Compressed Gas, N.O.S.

(Nitric Oxide, Nitrogen)

2.2

Net Weight: 2.5 Kg

NDC 64693-002-02

MADE IN USA

Label No. SPC-LBL-0060 R8

Cat Complex 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.


Cat Complex 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.


Cat Complex 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.


Cat Complex 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.


Cat Complex 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. "NITRIC ACID". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "411VRN1TV4: The UNique Ingredient Identifier (UNII) is an alphanumeric substance identifier from the joint FDA/USP Substance Registration System (SRS).". https://www.fda.gov/ForIndustry/Dat... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Cat Complex?

Depending on the reaction of the Cat Complex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Cat Complex 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 Cat Complex 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 Cat Complex, 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 Cat Complex 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. Rachana Salvi, MD Pharmacology

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