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GONADOTROPIN RELEASING HORMONE RECEPTOR ANTAGONISTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cetrorelix, degarelix, and ganirelix are synthetic decapeptides with gonadotropin-releasing hormone antagonistic activity in the pituitary pathway.

Specific Substances

    A) ABARELIX (synonym)
    1) Abarelixum
    2) PPI-149
    3) R-3827
    4) CAS 183552-38-7
    CETRORELIX (synonym)
    1) Acetato de cetrorelix
    2) Cetrorelix, Acetate de
    3) D-20761
    4) NS-75A
    5) SB-075
    6) SB-75
    7) CAS 120287-85-6 (Cetrorelix)
    8) CAS 145672-81-7 (Cetrorelix acetate)
    DEGARELIX (synonym)
    1) Degarelixum
    2) FE-200486 (degarelix acetate)
    3) CAS 214766-78-6
    GANIRELIX (synonym)
    1) Acetato de ganirelix
    2) Ganirelix, Acetate de
    3) Org-37462
    4) RS-26306
    5) CAS 124904-93-4 (ganirelix)
    6) CAS 129311-55-3 (ganirelix acetate)

    1.2.1) MOLECULAR FORMULA
    1) ABARELIX - C72-H95-Cl-N14-O14
    2) CETRORELIX: C70-H92-Cl-N17-O14, xC2-H4-O2
    3) DEGARELIX: C82-H103-Cl-N18-O16
    4) GANIRELIX: C80-H113-Cl-N18-O13, 2C-2H4-O2

Available Forms Sources

    A) FORMS
    1) CETRORELIX ACETATE
    a) Cetrorelix acetate is available in the US as a sterile lyophilized powder to be reconstituted with Sterile water for injection, a 1 mL (for 0.25 mg vial) pre-filled syringe (Prod Info Cetrotide(R) subcutaneous injection, 2014).
    2) DEGARELIX
    a) Degarelix is available in the US as a powder to be reconstituted with sterile water for injection, in either two vials each with 120 mg powder for injection or one vial with 80 mg powder for injection (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    3) GANIRELIX ACETATE
    a) Ganirelix acetate is available in the US as disposable sterile, prefilled 1 mL glass syringes containing 250 mcg/0.5 mL of ganirelix acetate (Prod Info ganirelix acetate subcutaneous injection, 2014).
    B) USES
    1) ABARELIX
    a) Abarelix has been used for the palliative treatment of men with advanced symptomatic prostate cancer (Prod Info Plenaxis(TM), 2003).
    2) CETRORELIX ACETATE
    a) Cetrorelix acetate is used for the inhibition of premature luteinizing hormone surges in women undergoing controlled ovarian stimulation (Prod Info Cetrotide(R) subcutaneous injection, 2014).
    3) DEGARELIX
    a) Degarelix is used for the treatment of patients with advanced prostate cancer (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    4) GANIRELIX ACETATE
    a) Ganirelix acetate is used for the inhibition of premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation (Prod Info ganirelix acetate subcutaneous injection, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Degarelix is used for the treatment of men with advanced prostate cancer. Cetrorelix and ganirelix are used for the inhibition of premature luteinizing hormone surges in women undergoing controlled ovarian stimulation. Abarelix is no longer sold in the US.
    B) PHARMACOLOGY: Gonadotropin-releasing hormone (GnRH) receptor antagonists competitively block GnRH receptors in the pituitary pathway, suppressing the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
    C) EPIDEMIOLOGY: No overdose cases have been reported. Poisoning may occur as a result of an iatrogenic error, but is extremely rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: DEGARELIX: Injection site reactions (eg; pain, erythema, swelling or induration), hot flashes, increased weight, increased liver enzymes, sleep disturbance, breast enlargement, back pain, constipation, peripheral edema. The following adverse effects have also been reported: Dizziness, headache, arthralgia, upper respiratory infection, diarrhea, dysuria, increased micturition, urinary retention, urinary tract infection, fatigue, abdominal pain, constipation, nausea, immediate-onset systemic allergic reactions (hypotension and syncope), upper respiratory infection, fever and chills, hypertension, prolonged QT interval (rare). GANIRELIX: Abdominal pain, headache, nausea, injection site reactions and ovarian hyperstimulation syndrome are the most common adverse effects. CETRORELIX: Headache, nausea and ovarian hyperstimulation are the most common adverse effects.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: There are no reports of overdose with these agents. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects. Toxic effects are typically mild to moderate.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) DEGARELIX: Fever and chills have been reported in patients receiving degarelix.
    0.2.20) REPRODUCTIVE
    A) Cetrorelix, degarelix, and ganirelix are classified as FDA pregnancy category X. These agents are contraindicated in pregnant women. Fetal malformations have been observed in clinical follow-up studies of newborns of women who were administered cetrorelix. Follow-up data on newborns of women who received ganirelix injections revealed 3 neonates with major congenital anomalies and 18 with minor anomalies.

Laboratory Monitoring

    A) Monitor fluid and electrolyte status in patients with severe vomiting.
    B) Monitor liver enzymes.
    C) Evaluate for evidence of ovarian hyperstimulation after cetrorelix or ganirelix overdose.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Overdose effects are anticipated to be an extension of adverse effects.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Hypersensitivity reactions, including anaphylaxis, have been reported with therapeutic use and may develop in overdose. Androgen deprivation may lead to prolonged QT interval. Obtain a baseline ECG in patients with an acute on chronic exposure or as indicated. Correct any electrolyte abnormalities. Monitor liver enzymes as indicated.
    C) DECONTAMINATION
    1) Decontamination is not indicated since these medications are given via the intramuscular and subcutaneous routes.
    D) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary. Patients may require airway support and intubation if severe anaphylaxis develops.
    E) ANTIDOTE
    1) None.
    F) ANAPHYLAXIS
    1) MILD/MODERATE: Monitor airway. Administer antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are not likely to be of value because of relatively high protein binding and large volumes of distribution.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure (ie, a single extra injection), that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Asymptomatic patients may be discharged following 6 hours of observation.
    3) ADMISSION CRITERIA: Patients may require admission if severe anaphylaxis occurs requiring airway management.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) Failure to consider GnRH receptor antagonists agents as an etiology for elevated liver enzymes, prolonged QT, or hypertension. Careful medication history is required to determine the cause of symptoms.
    J) PHARMACOKINETICS
    1) ABARELIX: Volume of distribution: 4040 +/- 1607 L; renal excretion 13% unchanged, elimination half life 13.2 +/- 3.2 days.
    2) CETRORELIX: Protein binding 86%; volume of distribution 1 L/kg; renal excretion 2% to 4% unchanged, elimination half life 5 hours (range 2.4 to 48.8 hours).
    3) DEGARELIX: Protein binding 90%, volume of distribution more than 1 L/kg; renal elimination 20% to 30%; elimination half life 53 days (slow release from depot formed at injection site).
    4) GANIRELIX: Protein binding 81.9%; volume of distribution 43.7 L; renal elimination 22.1%; elimination half life single dose 12.8 hours, multiple dose 16.2 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause elevated liver enzymes (eg, ethanol, acetaminophen), prolonged QT (eg, quinidine, amiodarone), or hypertension (eg, amphetamines, epinephrine, clonidine).

Range Of Toxicity

    A) TOXICITY: No maximum tolerated doses have been established. In clinical studies, the maximum dose of abarelix used in patients was 150 mg. No adverse events were observed in patients after receiving single cetrorelix doses up to 120 mg.
    B) THERAPEUTIC DOSE: Abarelix: 100 mg IM on day 1, 15, 29 (week 4) and every 4 weeks thereafter. Cetrorelix acetate: Single dose regimen: 3 mg SubQ when the serum estradiol level is indicative of an appropriate stimulation response, usually on stimulation day 7 (range day 5 to 9). If hCG has not been administered within 4 days after injection of cetrorelix 3 mg, then 0.25 mg SubQ once daily should be administered until the day of hCG administration. Multiple dose regimen: 0.25 mg subQ every day starting on either stimulation day 5 (morning or evening) or day 6 (morning) and continued until the day of hCG administration. Degarelix: Initial dose: 240 mg SubQ given as 2 injections of 120 mg each. Maintenance dose: 80 mg SubQ given as a single injection every 28 days; Ganirelix: 250 mcg SubQ once daily during mid to late portion of the follicular phase, after initiating FSH therapy on day 2 or 3 of the cycle, until the day of hCG administration.

Clinical Effects

Summary Of Exposure

    A) USES: Degarelix is used for the treatment of men with advanced prostate cancer. Cetrorelix and ganirelix are used for the inhibition of premature luteinizing hormone surges in women undergoing controlled ovarian stimulation. Abarelix is no longer sold in the US.
    B) PHARMACOLOGY: Gonadotropin-releasing hormone (GnRH) receptor antagonists competitively block GnRH receptors in the pituitary pathway, suppressing the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
    C) EPIDEMIOLOGY: No overdose cases have been reported. Poisoning may occur as a result of an iatrogenic error, but is extremely rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: DEGARELIX: Injection site reactions (eg; pain, erythema, swelling or induration), hot flashes, increased weight, increased liver enzymes, sleep disturbance, breast enlargement, back pain, constipation, peripheral edema. The following adverse effects have also been reported: Dizziness, headache, arthralgia, upper respiratory infection, diarrhea, dysuria, increased micturition, urinary retention, urinary tract infection, fatigue, abdominal pain, constipation, nausea, immediate-onset systemic allergic reactions (hypotension and syncope), upper respiratory infection, fever and chills, hypertension, prolonged QT interval (rare). GANIRELIX: Abdominal pain, headache, nausea, injection site reactions and ovarian hyperstimulation syndrome are the most common adverse effects. CETRORELIX: Headache, nausea and ovarian hyperstimulation are the most common adverse effects.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: There are no reports of overdose with these agents. The signs and symptoms of an acute overdose are expected to be similar to excessive pharmacologic effects. Toxic effects are typically mild to moderate.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) DEGARELIX: Fever and chills have been reported in patients receiving degarelix.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) DEGARELIX: Fever was reported in 1% to 5% of patients who received subQ degarelix 240 mg followed by 160 mg once monthly (n=202) or subQ degarelix 240 mg followed by 80 mg once monthly (n=207) for one year in a randomized, active-controlled trial of men with prostate cancer (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    2) DEGARELIX: In a randomized, active-controlled trial of men with prostate cancer, chills were reported in 4% of patients who received subQ degarelix 240 mg followed by 160 mg once monthly (n=202), 5% of patients who received subQ degarelix 240 mg followed by 80 mg once monthly (n=207), and 0% of patients who received IM leuprolide 7.5 mg once monthly (n=201) for one year (Prod Info FIRMAGON(R) subcutaneous injection, 2015).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) ABARELIX: In an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), peripheral edema developed in 15% of patients receiving abarelix 100 mg intramuscularly (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    B) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Androgen deprivation may prolong the QT interval (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    b) ABARELIX: Prolonged QT interval has been reported in patients receiving abarelix (Prod Info Plenaxis(TM), 2003).
    c) DEGARELIX: Androgen deprivation may prolong the QT interval. n a randomized, active-controlled trial of men with prostate cancer (n=610), 3 patients (less than 1%) who received subQ degarelix and 4 patients (2%) who received IM leuprolide for one year had a QTcF of 500 milliseconds (msec) or greater; additionally, the median QTcF change from baseline was 12.3 msec and 16.7 msec, respectively (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    C) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) DEGARELIX: In a randomized, active-controlled trial of men with prostate cancer, hypertension was reported in 7% of patients who received subQ degarelix 240 mg followed by 160 mg once monthly (n=202), 6% of patients who received subQ degarelix 240 mg followed by 80 mg once monthly (n=207), and 4% of patients who received IM leuprolide 7.5 mg once monthly (n=201) for one year (Prod Info FIRMAGON(R) subcutaneous injection, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) ABARELIX: In an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), headache developed in 12% of patients receiving abarelix 100 mg intramuscularly (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    b) GANIRELIX: In two randomized, parallel-group, multicenter, controlled, clinical studies, headache was reported in 3% (24/794) of patients treated with ganirelix from 1 to 14 days (Prod Info ganirelix acetate subcutaneous injection, 2014).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) ABARELIX: n an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), dizziness developed in 12% of patients receiving abarelix 100 mg IM (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    C) DYSSOMNIA
    1) WITH THERAPEUTIC USE
    a) ABARELIX: In an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), sleep disturbance developed in 44% of patients receiving abarelix 100 mg IM (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    D) FATIGUE
    1) WITH THERAPEUTIC USE
    a) ABARELIX: In an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), fatigue developed in 10% of patients receiving abarelix 100 mg intramuscularly (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    b) DEGARELIX: In a randomized, active-controlled trial of men with prostate cancer, fatigue was reported in 6% of patients who received subQ degarelix 240 mg followed by 160 mg once monthly (n=202), 3% of patients who received subQ degarelix 240 mg followed by 80 mg once monthly (n=207), and 6% of patients who received IM leuprolide 7.5 mg once monthly (n=201) for one year (Prod Info FIRMAGON(R) subcutaneous injection, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) GANIRELIX: In two randomized, parallel-group, multicenter, controlled, clinical studies, abdominal pain (gynecological) was reported in 4.8% (38/794) of patients treated with ganirelix from 1 to 14 days (Prod Info ganirelix acetate subcutaneous injection, 2014).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) ABARELIX: In an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), constipation developed in 15% of patients receiving abarelix 100 mg intramuscularly (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    b) DEGARELIX: In a randomized, active-controlled trial of men with prostate cancer, constipation was reported in 3% of patients who received subQ degarelix 240 mg followed by 160 mg once monthly (n=202), 5% of patients who received subQ degarelix 240 mg followed by 80 mg once monthly (n=207), and 5% of patients who received IM leuprolide 7.5 mg once monthly (n=201) for one year (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) ABARELIX: In an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), diarrhea developed in 11% of patients receiving abarelix 100 mg intramuscularly (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    D) NAUSEA
    1) WITH THERAPEUTIC USE
    a) ABARELIX: In an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), nausea developed in 10% of patients receiving abarelix 100 mg intramuscularly (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    b) CETRORELIX: Nausea was reported in 1.3% of patients in clinical trials (n=949) (Prod Info Cetrotide(R) subcutaneous injection, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) ABARELIX: Increases in serum transaminases have been reported in a small percentage of patients receiving abarelix. Two randomized, open-label, active-comparator trials (n=348) evaluated the effectiveness of abarelix. Patients in study one were randomized in a 2:1 ratio to receive either abarelix 100 mg IM or LHRH agonist. In study two, patients received either abarelix or LHRH agonist plus nonsteroidal antiandrogens. Elevated serum alanine aminotransferase (ALT) levels greater than 2.5 times upper limit of normal or greater than 200 Units/liter (L) were reported in 8.2% and 1.8% of patients receiving abarelix, respectively. Elevated serum aspartate aminotransferase (AST) levels greater than 2.5 times upper limit of normal or greater than 200 Units/L were reported in 3.1% and 0.8% of patients receiving abarelix, respectively. Patients in active comparators had similar results (Prod Info Plenaxis(TM), 2003).
    b) CETRORELIX: Liver enzyme elevations ranging up to 3 times the upper limit of normal occurred in 1% to 2% of patients in clinical trials (Prod Info Cetrotide(R) subcutaneous injection, 2014).
    c) DEGARELIX: In a randomized, active-controlled trial of men with prostate cancer, increases in transaminase and gamma-glutamyltransferase concentrations were reported in 10% of patients who received subQ degarelix 240 mg followed by 160 mg once monthly (n=202), 10% of patients who received subQ degarelix 240 mg followed by 80 mg once monthly (n=207), and 5% of patients who received IM leuprolide 7.5 mg once monthly (n=201) for one year (Prod Info FIRMAGON(R) subcutaneous injection, 2015).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) GENITOURINARY TRACT PROBLEM
    1) WITH THERAPEUTIC USE
    a) ABARELIX: In an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), dysuria (10%), increased micturition (10%), urinary retention (10%), urinary tract infection (10%) were reported in patients receiving abarelix 100 mg intramuscularly (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    b) DEGARELIX: In a randomized, active-controlled trial of men with prostate cancer, urinary tract infection was reported in 2% of patients who received subQ degarelix 240 mg followed by 160 mg once monthly (n=202), 5% of patients who received subQ degarelix 240 mg followed by 80 mg once monthly (n=207), and 9% of patients who received IM leuprolide 7.5 mg once monthly (n=201) for one year (Prod Info FIRMAGON(R) subcutaneous injection, 2015).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) CETRORELIX: Local site reactions manifesting as redness, erythema, bruising, itching, swelling, and pruritus have been reported in patients receiving cetrorelix. These reactions were of a transient nature, mild intensity, and short duration (Prod Info Cetrotide(R) subcutaneous injection, 2014).
    b) CETRORELIX: Erythema at the subcutaneous injection site has been reported occasionally (Behre et al, 1997; Olivennes et al, 1994; Gonzalez-Barcena et al, 1995). Spontaneous resolution is usually seen in 1 or 2 hours.
    c) DEGARELIX: In a randomized, active-controlled trial of men with prostate cancer, injection-site reactions were reported in 44% of patients who received subQ degarelix 240 mg followed by 160 mg once monthly (n=202), 35% of patients who received subQ degarelix 240 mg followed by 80 mg once monthly (n=207), and less than 1% of patients who received IM leuprolide 7.5 mg once monthly (n=201) for one year. Additionally, pain (28%), erythema (17%), swelling (6%), induration (4%), and nodule (3%) were the most commonly reported injection-site reactions (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    B) FLUSHING
    1) WITH THERAPEUTIC USE
    a) ABARELIX: In an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), hot flushes (79%) were reported in patients receiving abarelix 100 mg intramuscularly (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    b) CETRORELIX: Hot flushes related to estrogen deprivation have been common in women treated with cetrorelix for uterine fibroids; loss of libido has also been observed (Felberbaum et al, 1998; Gonzalez-Barcena et al, 1997). In another study, hot flushes were seen in 37% of men with benign prostatic hyperplasia during therapy with 1 mg subcutaneously daily (Comaru-Schally et al, 1998).
    c) DEGARELIX: In a randomized, active-controlled trial of men with prostate cancer, hot flashes were reported in 26% of patients who received subQ degarelix 240 mg followed by 160 mg once monthly (n=202), 26% of patients who received subQ degarelix 240 mg followed by 80 mg once monthly (n=207), and 21% of patients who received IM leuprolide 7.5 mg once monthly (n=201) for one year (Prod Info FIRMAGON(R) subcutaneous injection, 2015).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) ABARELIX: In an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), back pain developed in 17% of patients receiving abarelix 100 mg intramuscularly (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    b) DEGARELIX: In a randomized, active-controlled trial of men with prostate cancer, back pain was reported in 6% of patients who received subQ degarelix 240 mg followed by 160 mg once monthly (n=202), 6% of patients who received subQ degarelix 240 mg followed by 80 mg once monthly (n=207), and 8% of patients who received IM leuprolide 7.5 mg once monthly (n=201) for one year (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) DEGARELIX: In a randomized, active-controlled trial of men with prostate cancer, arthralgia was reported in 4% of patients who received subQ degarelix 240 mg followed by 160 mg once monthly (n=202), 5% of patients who received subQ degarelix 240 mg followed by 80 mg once monthly (n=207), and 9% of patients who received IM leuprolide 7.5 mg once monthly (n=201) for one year (Prod Info FIRMAGON(R) subcutaneous injection, 2015).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) ENDOCRINE FINDING
    1) WITH THERAPEUTIC USE
    a) ABARELIX: In an open-label, multicenter, uncontrolled, single-arm study (n=81; Advanced Symptomatic Prostate Cancer Study), breast enlargement (30%) and breast pain/nipple tenderness (20%) were reported in patients receiving abarelix 100 mg intramuscularly (days 1, 15, and 29, then every 4 weeks). However, causality was not established (Prod Info Plenaxis(TM), 2003).
    B) OVARIAN HYPERSTIMULATION SYNDROME
    1) WITH THERAPEUTIC USE
    a) CETRORELIX: World Health Organization (WHO) Grade II or III Ovarian Hyperstimulation Syndrome was documented in 3.5% of patients in clinical trials (n=949)(Prod Info Cetrotide(R) subcutaneous injection, 2014).
    b) GANIRELIX: In two randomized, parallel-group, multicenter, controlled, clinical studies, Ovarian Hyperstimulation Syndrome was reported in 2.4% (19/794) of patients treated with ganirelix from 1 to 14 days (Prod Info ganirelix acetate subcutaneous injection, 2014).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) ABARELIX: Immediate-onset systemic allergic reactions, some resulting in hypotension and syncope, have been reported following the administration of abarelix. In a clinical trial, 3 of 81 (3.7%) patients with advanced, symptomatic prostate cancer developed an immediate-onset systemic allergic reaction (urticaria (day 15); urticaria and pruritus (day 29); hypotension and syncope (day 141)) after receiving abarelix (Prod Info Plenaxis(TM), 2003).
    b) CETRORELIX: During post-marketing surveillance, hypersensitivity reactions, including anaphylactoid reactions, have been reported (Prod Info Cetrotide(R) subcutaneous injection, 2014).
    c) GANIRELIX: Hypersensitivity reactions, including anaphylactoid reactions with the first dose, have been observed during post-marketing surveillance (Prod Info ganirelix acetate subcutaneous injection, 2014).
    B) ANTIBODY DEVELOPMENT
    1) WITH THERAPEUTIC USE
    a) DEGARELIX: Anti-degarelix antibodies occurred in 10% of patients treated for one year with subQ degarelix (Prod Info degarelix acetate subcutaneous injection powder for solution, 2008).

Reproductive

    3.20.1) SUMMARY
    A) Cetrorelix, degarelix, and ganirelix are classified as FDA pregnancy category X. These agents are contraindicated in pregnant women. Fetal malformations have been observed in clinical follow-up studies of newborns of women who were administered cetrorelix. Follow-up data on newborns of women who received ganirelix injections revealed 3 neonates with major congenital anomalies and 18 with minor anomalies.
    3.20.2) TERATOGENICITY
    A) CETRORELIX
    1) Clinical follow up studies of newborns (n=316) of women who were administered cetrorelix were performed. One infant from a set of twins had anencephaly at birth and died after four days, while the other twin was normal. Ongoing follow-up of other neonates showed one child with a ventricular septal defect, and another with a bilateral congenital glaucoma. Major anomalies (diaphragmatic hernia, trisomy 21, Klinefelter syndrome, polymalformation and trisomy 18) were observed after four pregnancies that resulted in therapeutic abortion in Phase 2 and Phase 3 controlled ovarian stimulation studies. Minor congenital anomalies were also found in the neonates. The findings included supernumerary nipple, bilateral strabismus, imperforate hymen, congenital nevi, hemangiomata, and QT syndrome. A causal relationship between the above listed anomalies in neonates and cetrorelix has not been determined. Many factors are contributors such as genetics, fertilization methods, gonadotropins and progesterones, thus making causal attribution difficult to study (Prod Info Cetrotide(R) subcutaneous injection, 2014).
    B) GANIRELIX
    1) Follow-up data of 283 newborns of women who received ganirelix injections revealed 3 neonates with major congenital anomalies and 18 with minor anomalies. The following major congenital anomalies were reported: hydrocephalus/meningocele, omphalocele, and Beckwith-Wiedemann Syndrome. The following minor congenital anomalies were also reported: nevus, skin tags, sacral sinus, hemangioma, torticollis/asymmetric skull, talipes, supernumerary digit finger, hip subluxation, torticollis/high palate, occiput/abnormal hand crease, hernia umbilicalis, hernia inguinalis, hydrocele, undescended testis, and hydronephrosis. A causal relationship between these listed anomalies in neonates and ganirelix has not been determined (Prod Info ganirelix acetate subcutaneous injection, 2014).
    C) ANIMAL STUDIES
    1) DEGARELIX
    a) An increase in the number of minor skeletal abnormalities and variants was observed in rats following degarelix doses of 0.045 mg/kg/day (approximately 0.36% of the clinical loading dose) during mid and late organogenesis (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    2) GANIRELIX
    a) No increases in fetal abnormalities were observed after ganirelix doses up to 10 and 30 mcg/day (approximately 0.4 to 3.2 times the human dose) were administered from day 7 to near term to pregnant rats and rabbits, respectively (Prod Info ganirelix acetate subcutaneous injection, 2007).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Abarelix, cetrorelix, degarelix, and ganirelix are classified as FDA pregnancy category X. These drug agents are contraindicated in pregnant women (Prod Info Cetrotide(R) subcutaneous injection, 2014; Prod Info FIRMAGON(R) subcutaneous injection, 2015; Prod Info ganirelix acetate subcutaneous injection, 2014; Prod Info Plenaxis(TM), 2003).
    B) ANIMAL STUDIES
    1) ABARELIX
    a) Abarelix doses up to 3 mg/kg (0.228 times the human dose) given subcutaneously to pregnant rats resulted in embryolethality. Increased fetal resorptions and decreased viability were seen when pregnant rabbits were administered abarelix doses up to 30 mg/kg subcutaneously (6.81 times the human dose) (Prod Info Plenaxis(TM), 2003).
    2) CETRORELIX
    a) Cetrorelix doses up to 38 mcg/kg (approximately 1 time the human dose) given to pregnant rats did not affect the development of the implanted conceptus. However, a resorption rate and a post-implantation loss of 100% were observed following a dose of 139 mcg/kg (approximately 4 times the human dose). Cetrorelix doses from 4.6 mcg/kg (0.2 times the human dose) given to pregnant rats and doses from 6.8 mcg/kg (0.4 times the human dose) given to pregnant rabbits from day 6 to near-term, resulted in very early resorptions and total implantation losses (Prod Info Cetrotide(R) subcutaneous injection, 2014).
    3) DEGARELIX
    a) In studies of rabbits, an increase in early post-implantation loss was observed following degarelix use at doses of 0.002 mg/kg/day (approximately 0.02% of the clinical loading dose on a mg/m(2) basis) during early organogenesis. Embryo/fetal lethality and abortions were observed in rabbits following degarelix use at doses of 0.006 mg/kg/day (approximately 0.05% of the clinical loading dose) during mid and late organogenesis. In studies of female rats, an increase in early post-implantation loss was observed following degarelix use at doses of 0.0045 mg/kg/day (approximately 0.036% of the clinical loading dose) during early organogenesis (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    4) GANIRELIX
    a) The incidence of litter resorption was increased after ganirelix doses up to 10 and 30 mcg/day (approximately 0.4 to 3.2 times the human dose) were administered from day 7 to near term to pregnant rats and rabbits, respectively (Prod Info ganirelix acetate subcutaneous injection, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) ANIMAL STUDIES
    1) It's unknown whether abarelix, cetrorelix, degarelix, and ganirelix are excreted in human milk and the potential for adverse effects in the nursing infant from exposure to these drugs are unknown. These drugs should not be used by nursing mothers (Prod Info FIRMAGON(R) subcutaneous injection, 2015; Prod Info Cetrotide(R) subcutaneous injection, 2014; Prod Info ganirelix acetate subcutaneous injection, 2014; Prod Info Plenaxis(TM), 2003).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) ABARELIX: There were no effects on mating or fertility in male and female rats given 1 mg/kg subcutaneous abarelix (0.114-fold the human therapeutic dose). Mating and fertility were significantly reduced at doses of 3 and 10 mg/kg (0.34 and 1.135 times the human therapeutic dose, respectively), but these effects were reversible (Prod Info Plenaxis(TM), 2003).
    2) CETRORELIX: Female rats treated with 0.46 mg/kg cetrorelix for 4 weeks developed complete infertility which was reversed 8 weeks after the treatment was stopped (Prod Info Cetrotide(R) subcutaneous injection, 2014).
    3) DEGARELIX: Reversible infertility was observed in male rats following single degarelix doses of 1 mg/kg or greater (about 5% of the clinical loading dose). A decrease in fertility was observed in female rats following single doses of 0.1 mg/kg or greater (about 0.5% of the clinical loading dose) (Prod Info FIRMAGON(R) subcutaneous injection, 2015).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS183552-38-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS120287-85-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    C) IARC Carcinogenicity Ratings for CAS214766-78-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    D) IARC Carcinogenicity Ratings for CAS124904-93-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) MALIGNANT HEMANGIOSARCOMAS
    1) DEGARELIX: In animal studies, rats received degarelix 2, 10 and 25 mg/kg (about 9%, 45%, and 120% of the recommended human loading dose) subcutaneously every 2 weeks for 2 years. An increase in the combined incidence of benign hemangiomas plus malignant hemangiosarcomas in female rats was observed following degarelix doses of 25 mg/kg (about 120% of the recommended human loading dose) (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    B) LACK OF EFFECT
    1) ABARELIX: There was no evidence of carcinogenicity when mice and rats were given abarelix doses up to 300 mg/kg and 100 mg/kg, respectively, as a subcutaneous depot every 28 days for 2 years (Prod Info Plenaxis(TM), 2003).
    2) CETRORELIX: Long-term animal carcinogenicity studies have not been performed with cetrorelix (Prod Info Cetrotide(R) subcutaneous injection, 2014).
    3) DEGARELIX: In animal studies, mice received degarelix 2, 10 and 50 mg/kg (about 5%, 22%, and 120% of the recommended human loading dose) subcutaneously every 2 weeks for 2 years; no statistically significant increase in tumor incidence was observed (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    4) GANIRELIX: Long-term animal carcinogenicity studies have not been performed with ganirelix (Prod Info ganirelix acetate subcutaneous injection, 2014).

Genotoxicity

    A) ABARELIX: It was not mutagenic in the in vitro bacterial Ames assay or forward mutation assay in mouse lymphoma, or clastogenic in the in vivo mouse micronucleus assay (Prod Info Plenaxis(TM), 2003).
    B) CETRORELIX: There was no evidence of genotoxicity with the Ames Test, HPRT Test, and chromosome aberration test, as well as mutagenicity in vivo in the chromosome aberration test and mouse micronucleus test. Cetrorelix did not induce polyploidy in V79–Chinese hamster lung fibroblasts, cultured peripheral human lymphocytes or in an in-vitro micronucleus test in the CHL-cell line, but it did induce polyploidy in CHL-Chinese hamster lung fibroblasts (Prod Info Cetrotide(R) subcutaneous injection, 2014).
    C) DEGARELIX: There was no evidence of genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte, chromosome aberration) nor in in vivo rodent bone marrow micronucleus tests (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    D) GANIRELIX: Ganirelix was not mutagenic in the Ames test (S. typhimurium and E. coli) and did not produce chromosomal aberrations in an in vitro assay using Chinese Hamster Ovary cells (Prod Info ganirelix acetate subcutaneous injection, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor fluid and electrolyte status in patients with severe vomiting.
    B) Monitor liver enzymes.
    C) Evaluate for evidence of ovarian hyperstimulation after cetrorelix or ganirelix overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients may require admission if severe anaphylaxis occurs requiring airway management.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) A patient with an inadvertent exposure (ie, a single extra injection), that remains asymptomatic can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Asymptomatic patients may be discharged following 6 hours of observation.

Monitoring

    A) Monitor fluid and electrolyte status in patients with severe vomiting.
    B) Monitor liver enzymes.
    C) Evaluate for evidence of ovarian hyperstimulation after cetrorelix or ganirelix overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not indicated since these medications are given via the intramuscular and subcutaneous routes.

Range Of Toxicity

Summary

    A) TOXICITY: No maximum tolerated doses have been established. In clinical studies, the maximum dose of abarelix used in patients was 150 mg. No adverse events were observed in patients after receiving single cetrorelix doses up to 120 mg.
    B) THERAPEUTIC DOSE: Abarelix: 100 mg IM on day 1, 15, 29 (week 4) and every 4 weeks thereafter. Cetrorelix acetate: Single dose regimen: 3 mg SubQ when the serum estradiol level is indicative of an appropriate stimulation response, usually on stimulation day 7 (range day 5 to 9). If hCG has not been administered within 4 days after injection of cetrorelix 3 mg, then 0.25 mg SubQ once daily should be administered until the day of hCG administration. Multiple dose regimen: 0.25 mg subQ every day starting on either stimulation day 5 (morning or evening) or day 6 (morning) and continued until the day of hCG administration. Degarelix: Initial dose: 240 mg SubQ given as 2 injections of 120 mg each. Maintenance dose: 80 mg SubQ given as a single injection every 28 days; Ganirelix: 250 mcg SubQ once daily during mid to late portion of the follicular phase, after initiating FSH therapy on day 2 or 3 of the cycle, until the day of hCG administration.

Therapeutic Dose

    7.2.1) ADULT
    A) ABARELIX
    1) 100 mg administered intramuscularly to the buttock on day 1, 15, 29 (week 4) and every 4 weeks thereafter (Prod Info Plenaxis(TM), 2003).
    B) CETRORELIX ACETATE
    1) 0.25 mg SubQ administered every day starting on either stimulation day 5 (morning or evening) or day 6 (morning) and continued until the day of hCG administration; adjust dose according to individual response (Prod Info Cetrotide(R) subcutaneous injection, 2014).
    C) DEGARELIX
    1) STARTING DOSE: 240 mg administered as two subcutaneous abdominal injections of 120 mg each. MAINTENANCE DOSE: 80 mg administered as a single subcutaneous abdominal injection every 28 days (Prod Info FIRMAGON(R) subcutaneous injection, 2015).
    D) GANIRELIX ACETATE
    1) 250 mcg SubQ administered once daily during mid to late portion of the follicular phase, after initiating FSH therapy on day 2 or 3 of the cycle, until the day of hCG administration (Prod Info ganirelix acetate subcutaneous injection, 2014).

Maximum Tolerated Exposure

    A) No maximum tolerated doses have been established.
    B) ABARELIX: In clinical studies, the maximum dose of abarelix used in patients was 150 mg (Prod Info Plenaxis(TM), 2003).
    C) CETRORELIX: No adverse events were observed in patients after receiving single cetrorelix doses up to 120 mg (Prod Info CETROTIDE(R) subcutaneous injection, 2004).

Workplace Standards

    A) ACGIH TLV Values for CAS183552-38-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS120287-85-6 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) ACGIH TLV Values for CAS214766-78-6 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    D) ACGIH TLV Values for CAS124904-93-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    E) NIOSH REL and IDLH Values for CAS183552-38-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    F) NIOSH REL and IDLH Values for CAS120287-85-6 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    G) NIOSH REL and IDLH Values for CAS214766-78-6 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    H) NIOSH REL and IDLH Values for CAS124904-93-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    I) Carcinogenicity Ratings for CAS183552-38-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    J) Carcinogenicity Ratings for CAS120287-85-6 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    K) Carcinogenicity Ratings for CAS214766-78-6 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    L) Carcinogenicity Ratings for CAS124904-93-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    M) OSHA PEL Values for CAS183552-38-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    N) OSHA PEL Values for CAS120287-85-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    O) OSHA PEL Values for CAS214766-78-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    P) OSHA PEL Values for CAS124904-93-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Abarelix, cetrorelix, degarelix, and ganirelix are synthetic decapeptides with antagonistic activity against gonadotropin-releasing hormone (GnRH). They directly suppress luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion and reduce the secretion of testosterone by the testes (Prod Info Cetrotide(R) subcutaneous injection, 2014; Prod Info FIRMAGON(R) subcutaneous injection, 2015; Prod Info ganirelix acetate subcutaneous injection, 2014; Prod Info Plenaxis(TM), 2003).

Physicochemical

Physical Characteristics

    A) ABARELIX: White to off-white sterile powder (Prod Info Plenaxis(TM), 2003)
    B) CETRORELIX: Sterile lyophilized powder for injection (Prod Info Cetrotide(R) subcutaneous injection, 2014)
    C) DEGARELIX: Sterile lyophilized white to off-white amorphous powder for injection (Prod Info FIRMAGON(R) subcutaneous injection, 2015)
    D) GANIRELIX: Colorless, sterile, aqueous solution (Prod Info ganirelix acetate subcutaneous injection, 2014)

Molecular Weight

    1) ABARELIX - 1416.1 (Prod Info Plenaxis(TM), 2003)
    2) CETRORELIX ACETATE: 143.06 (Prod Info Cetrotide(R) subcutaneous injection, 2014)
    3) DEGARELIX: 1632.3 (Prod Info FIRMAGON(R) subcutaneous injection, 2015)
    4) GANIRELIX ACETATE: 1570.4 (Prod Info ganirelix acetate subcutaneous injection, 2014)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    12) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    13) American Conference of Governmental Industrial Hygienists : ACGIH 2010 Threshold Limit Values (TLVs(R)) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs(R)), American Conference of Governmental Industrial Hygienists, Cincinnati, OH, 2010.
    14) Behre HM, Kliesch S, Puhse G, et al: High loading and low maintenance doses of a gonadotropin-releasing antagonist effectively suppress serum luteinizing hormone, follicle- stimulating hormone, and testosterone in normal men. J Clin Endocrin Metab 1997; 82(5):1403-1408.
    15) Comaru-Schally AM, Brannan W, Schally AV, et al: Efficacy and safety of luteinizing hormone- releasing hormone antagonist cetrorelix in the treatment of symptomatic benign prostatic hyperplasia. J Clin Endocrin Metab 1998; 83(11):3826-3831.
    16) DFG: List of MAK and BAT Values 2002, Report No. 38, Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Wiley-VCH, Weinheim, Federal Republic of Germany, 2002.
    17) EPA: Search results for Toxic Substances Control Act (TSCA) Inventory Chemicals. US Environmental Protection Agency, Substance Registry System, U.S. EPA's Office of Pollution Prevention and Toxics. Washington, DC. 2005. Available from URL: http://www.epa.gov/srs/.
    18) Felberbaum RE, Germer U, Ludwig M, et al: Treatment of uterine fibroids with a slow-release formulation of the gonadotrophin releasing hormone antagonist cetrorelix. Hum Reprod 1998; 13(6):1660-1668.
    19) Gonzalez-Barcena D, Alvarez RB, Ochoa EP, et al: Treatment of uterine leiomyomas with luteinizing hormone-releasing antagonist cetrorelix. Hum Reprod 1997; 12(9):2028-2035.
    20) Gonzalez-Barcena D, Cardenas-Cornejo I, Vadillo-Buenfil M, et al: Luteinizing hormone-releasing hormone antagonist cetrorelix as primary single therapy in patients with advanced prostatic cancer and paraplegia due to metastatic invasion of spinal cord. Urology 1995; 45(2):275-281.
    21) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: 1,3-Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide), 97, International Agency for Research on Cancer, Lyon, France, 2008.
    22) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxypropan-2-ol, 88, International Agency for Research on Cancer, Lyon, France, 2006.
    23) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Household Use of Solid Fuels and High-temperature Frying, 95, International Agency for Research on Cancer, Lyon, France, 2010a.
    24) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines, 89, International Agency for Research on Cancer, Lyon, France, 2007.
    25) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Some Non-heterocyclic Polycyclic Aromatic Hydrocarbons and Some Related Exposures, 92, International Agency for Research on Cancer, Lyon, France, 2010.
    26) IARC: List of all agents, mixtures and exposures evaluated to date - IARC Monographs: Overall Evaluations of Carcinogenicity to Humans, Volumes 1-88, 1972-PRESENT. World Health Organization, International Agency for Research on Cancer. Lyon, FranceAvailable from URL: http://monographs.iarc.fr/monoeval/crthall.html. As accessed Oct 07, 2004.
    27) International Agency for Research on Cancer (IARC): IARC monographs on the evaluation of carcinogenic risks to humans: list of classifications, volumes 1-116. International Agency for Research on Cancer (IARC). Lyon, France. 2016. Available from URL: http://monographs.iarc.fr/ENG/Classification/latest_classif.php. As accessed 2016-08-24.
    28) International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. Geneva, Switzerland. 2015. Available from URL: http://monographs.iarc.fr/ENG/Classification/. As accessed 2015-08-06.
    29) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    30) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    31) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    32) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 1, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2001.
    33) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 2, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2002.
    34) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 3, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2003.
    35) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 4, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2004.
    36) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,3-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    37) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,4-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    38) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Butylene Oxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648083cdbb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    39) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Dibromoethane (Proposed). United States Environmental Protection Agency. Washington, DC. 2007g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802796db&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    40) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,3,5-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    41) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 2-Ethylhexyl Chloroformate (Proposed). United States Environmental Protection Agency. Washington, DC. 2007b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037904e&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    42) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Acrylonitrile (Proposed). United States Environmental Protection Agency. Washington, DC. 2007c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648028e6a3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    43) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Adamsite (Proposed). United States Environmental Protection Agency. Washington, DC. 2007h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    44) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Agent BZ (3-quinuclidinyl benzilate) (Proposed). United States Environmental Protection Agency. Washington, DC. 2007f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ad507&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    45) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Allyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039d9ee&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    46) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    47) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Arsenic Trioxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480220305&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    48) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Automotive Gasoline Unleaded (Proposed). United States Environmental Protection Agency. Washington, DC. 2009a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cc17&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    49) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Biphenyl (Proposed). United States Environmental Protection Agency. Washington, DC. 2005j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1b7&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    50) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bis-Chloromethyl Ether (BCME) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648022db11&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    51) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Boron Tribromide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae1d3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    52) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromine Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2007d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039732a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    53) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromoacetone (Proposed). United States Environmental Protection Agency. Washington, DC. 2008e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187bf&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    54) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Calcium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    55) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae328&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    56) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Sulfide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037ff26&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    57) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Chlorobenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803a52bb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    58) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Cyanogen (Proposed). United States Environmental Protection Agency. Washington, DC. 2008f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187fe&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    59) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Dimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbf3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    60) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Diphenylchloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    61) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091884e&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    62) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Phosphorodichloridate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480920347&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    63) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809203e7&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    64) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    65) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Germane (Proposed). United States Environmental Protection Agency. Washington, DC. 2008j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963906&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    66) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Hexafluoropropylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1f5&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    67) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ketene (Proposed). United States Environmental Protection Agency. Washington, DC. 2007. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ee7c&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    68) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    69) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    70) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Malathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2009k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809639df&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    71) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Mercury Vapor (Proposed). United States Environmental Protection Agency. Washington, DC. 2009b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a087&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    72) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Isothiocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a03&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    73) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a57&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    74) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl tertiary-butyl ether (Proposed). United States Environmental Protection Agency. Washington, DC. 2007a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802a4985&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    75) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methylchlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5f4&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    76) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    77) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c646&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    78) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN1 CAS Reg. No. 538-07-8) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    79) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN2 CAS Reg. No. 51-75-2) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    80) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN3 CAS Reg. No. 555-77-1) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    81) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Tetroxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091855b&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    82) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Trifluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e0c&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    83) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008o. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e32&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    84) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perchloryl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e268&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    85) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perfluoroisobutylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2009d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26a&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    86) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008p. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dd58&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    87) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2006d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020cc0c&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    88) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    89) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phorate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008q. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dcc8&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    90) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene (Draft-Revised). United States Environmental Protection Agency. Washington, DC. 2009e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a08a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    91) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene Oxime (Proposed). United States Environmental Protection Agency. Washington, DC. 2009f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26d&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    92) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    93) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    94) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Propargyl Alcohol (Proposed). United States Environmental Protection Agency. Washington, DC. 2006e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec91&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    95) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Selenium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec55&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    96) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Silane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d523&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    97) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    98) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    99) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Strontium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    100) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sulfuryl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec7a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    101) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tear Gas (Proposed). United States Environmental Protection Agency. Washington, DC. 2008s. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e551&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    102) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tellurium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e2a1&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    103) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tert-Octyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2008r. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5c7&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    104) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tetramethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-17.
    105) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    106) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7d608&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    107) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethylacetyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008t. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5cc&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    108) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Zinc Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    109) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for n-Butyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064808f9591&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    110) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    111) National Institute for Occupational Safety and Health: NIOSH Pocket Guide to Chemical Hazards, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Cincinnati, OH, 2007.
    112) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    113) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    114) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    115) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    116) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    117) Olivennes F, Taieb J, Fanchin R, et al: The single or dual administration of the gonadotropin-releasing hormone antagonist cetrorelix in an in vitro fertilization-embryo transfer program. Fertil Steril 1994; 62(3):468-476.
    118) Product Information: CETROTIDE(R) subcutaneous injection, cetrorelix acetate subcutaneous injection. Serono, Inc, Rockland, MA, 2004.
    119) Product Information: Cetrotide(R) subcutaneous injection, cetrorelix acetate subcutaneous injection. EMD Serono, Inc (per manufacturer), Rockland, MA, 2014.
    120) Product Information: FIRMAGON(R) subcutaneous injection, degarelix subcutaneous injection. Ferring Pharmaceuticals Inc. (per FDA), Parsippany, NJ, 2015.
    121) Product Information: Plenaxis(TM), abarelix for injectable suspension. Praecis Pharmaceuticals Incorporated, Waltham, MA, USA, 2003.
    122) Product Information: degarelix acetate subcutaneous injection powder for solution, degarelix acetate subcutaneous injection powder for solution. Ferring Pharamaceuticals, Parsippany, NJ, 2008.
    123) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    124) Product Information: ganirelix acetate subcutaneous injection, ganirelix acetate subcutaneous injection. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2014.
    125) Product Information: ganirelix acetate subcutaneous injection, ganirelix acetate subcutaneous injection. Organon USA Inc., Roseland, NJ, 2007.
    126) U.S. Department of Energy, Office of Emergency Management: Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: Rev. 26 for chemicals of concern. U.S. Department of Energy, Office of Emergency Management. Washington, DC. 2010. Available from URL: http://www.hss.doe.gov/HealthSafety/WSHP/Chem_Safety/teel.html. As accessed 2011-06-27.
    127) U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project : 11th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Washington, DC. 2005. Available from URL: http://ntp.niehs.nih.gov/INDEXA5E1.HTM?objectid=32BA9724-F1F6-975E-7FCE50709CB4C932. As accessed 2011-06-27.
    128) U.S. Environmental Protection Agency: Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. Environmental Protection Agency's (EPA) Resource Conservation and Recovery Act (RCRA); List of hazardous substances and reportable quantities 2010b; 40CFR(261.33, e-f):77-.
    129) U.S. Environmental Protection Agency: Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency. Washington, DC. 2011. Available from URL: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showSubstanceList&list_type=date. As accessed 2011-06-21.
    130) U.S. Environmental Protection Agency: List of Radionuclides. U.S. Environmental Protection Agency. Washington, DC. 2010a. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    131) U.S. Environmental Protection Agency: List of hazardous substances and reportable quantities. U.S. Environmental Protection Agency. Washington, DC. 2010. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    132) U.S. Environmental Protection Agency: The list of extremely hazardous substances and their threshold planning quantities (CAS Number Order). U.S. Environmental Protection Agency. Washington, DC. 2010c. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-part355.pdf. As accessed 2011-06-17.
    133) U.S. Occupational Safety and Health Administration: Part 1910 - Occupational safety and health standards (continued) Occupational Safety, and Health Administration's (OSHA) list of highly hazardous chemicals, toxics and reactives. Subpart Z - toxic and hazardous substances. CFR 2010 2010; Vol6(SEC1910):7-.
    134) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    135) United States Environmental Protection Agency Office of Pollution Prevention and Toxics: Acute Exposure Guideline Levels (AEGLs) for Vinyl Acetate (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6af&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    136) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.