Indications
Barhemsys is a selective dopamine-2 (D2) and dopamine-3 (D3) receptor antagonist indicated in adults for:

• prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class
• treatment of PONV in patients who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis

IMPORTANT SAFETY INFORMATION

Contraindication
Barhemsys is contraindicated in patients with known hypersensitivity to amisulpride.

QT Prolongation
Barhemsys causes dose- and concentration-dependent prolongation of the QT interval. The recommended dosage is 5 mg or 10 mg as a single intravenous (IV) dose infused over 1 to 2 minutes.

Avoid Barhemsys in patients with congenital long QT syndrome and in patients taking droperidol.

Electrocardiogram (ECG) monitoring is recommended in patients with pre-existing arrhythmias/cardiac conduction disorders, electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, and in patients taking other medicinal products (e.g., ondansetron) or with other medical conditions known to prolong the QT interval.

Adverse Reactions
Common adverse reactions reported in ≥ 2% of adult patients who received Barhemsys 5 mg (N=748) and at a higher rate than placebo (N=741) in clinical trials for the prevention of PONV were: chills (4% vs. 3%), hypokalemia (4% vs. 2%), procedural hypotension (3% vs. 2%), and abdominal distention (2% vs. 1%).

Serum prolactin concentrations were measured in one prophylaxis study where 5% (9/176) of Barhemsys-treated patients had increased blood prolactin reported as an adverse reaction compared with 1% (1/166) of placebo-treated patients.

The most common adverse reaction, reported in ≥ 2% of adult patients who received Barhemsys 10 mg (N=418) and at a higher rate than placebo (N=416), in clinical trials for the treatment of PONV was infusion site pain (6% vs. 4%).

Use in Specific Populations
Lactation
Amisulpride is present in human milk. There are no reports of adverse effects on the breastfed child and no information on the effects of amisulpride on milk production.

Barhemsys may result in an increase in serum prolactin levels, which may lead to a reversible increase in maternal milk production. In a clinical trial, serum prolactin concentrations in females (n=112) increased from a mean of 10 ng/mL at baseline to 32 ng/mL after Barhemsys treatment and from 10 ng/mL to 19 ng/mL in males (n=61). No clinical consequences due to elevated prolactin levels were reported.

To minimize exposure to a breastfed infant, lactating women may consider interrupting breastfeeding and pumping and discarding breast milk for 48 hours after receiving a dose of Barhemsys.

Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

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

Renal Impairment
Avoid Barhemsys in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2). The pharmacokinetics of amisulpride in patients with severe renal impairment have not been adequately studied in clinical trials. Amisulpride is known to be substantially excreted by the kidneys, and patients with severe renal impairment may have increased systemic exposure and an increased risk of adverse reactions.

No dosage adjustment is necessary in patients with mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2).

Drug Interactions

• Barhemsys causes dose- and concentration-dependent QT prolongation. To avoid potential additive effects, avoid use of Barhemsys in patients taking droperidol.
• ECG monitoring is recommended in patients taking other drugs known to prolong the QT interval (e.g., ondansetron).
• Reciprocal antagonism of effects occurs between dopamine agonists (e.g., levodopa) and Barhemsys. Avoid using levodopa with Barhemsys.

Please click to access full Prescribing Information.

BAR HCP ISI 02/2020

PONV=postoperative nausea and vomiting.

References: 1. Gan TJ, Belani KG, Bergese S, et al. Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting. Anesth Analg. 2020;131(2):411-448. 2. Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers. Anesthesiology. 1999;91(3):693-700. 3. Barhemsys [Prescribing Information], Indianapolis, IN. Acacia Pharma Inc. 4. Habib AS, Kranke P, Bergese SD, et al. Amisulpride for the rescue treatment of postoperative nausea or vomiting in patients failing prophylaxis: a randomized, placebo-controlled phase III trial. Anesthesiology. 2019;130(2):203-212.

Indication
Byfavo is a benzodiazepine indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less.

Important Safety Information
WARNING: PERSONNEL AND EQUIPMENT FOR MONITORING AND RESUSCITATION AND RISKS FROM CONCOMITANT USE WITH OPIOID ANALGESICS AND OTHER SEDATIVE-HYPNOTICS

Personnel and Equipment for Monitoring and Resuscitation

• Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer Byfavo.
• Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation.
• Byfavo has been associated with hypoxia, bradycardia, and hypotension. Continuously monitor vital signs during sedation and during the recovery period.
• Resuscitative drugs, and age- and size-appropriate equipment for bag-valve-mask–assisted ventilation must be immediately available during administration of Byfavo.

Risks From Concomitant Use With Opioid Analgesics and Other Sedative-Hypnotics
Concomitant use of benzodiazepines, including Byfavo, and opioid analgesics may result in profound sedation, respiratory depression, coma, and death. The sedative effect of intravenous Byfavo can be accentuated by concomitantly administered CNS depressant medications, including other benzodiazepines and propofol. Continuously monitor patients for respiratory depression and depth of sedation.

Contraindication
Byfavo is contraindicated in patients with a history of severe hypersensitivity reaction to dextran 40 or products containing dextran 40.

Personnel and Equipment for Monitoring and Resuscitation
Clinically notable hypoxia, bradycardia, and hypotension were observed in Phase 3 studies of Byfavo. Continuously monitor vital signs during sedation and through the recovery period. Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer Byfavo. Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation. Resuscitative drugs, and age- and size-appropriate equipment for bag-valve-mask–assisted ventilation must be immediately available during administration of Byfavo. Consider the potential for worsened cardiorespiratory depression prior to using Byfavo concomitantly with other drugs that have the same potential (eg, opioid analgesics or other sedative-hypnotics). Administer supplemental oxygen to sedated patients through the recovery period. A benzodiazepine reversal agent (flumazenil) should be immediately available during administration of Byfavo.

Risks From Concomitant Use With Opioid Analgesics and Other Sedative-Hypnotics
Concomitant use of Byfavo and opioid analgesics may result in profound sedation, respiratory depression, coma, and death. The sedative effect of IV Byfavo can be accentuated when administered with other CNS depressant medications (eg, other benzodiazepines and propofol). Titrate the dose of Byfavo when administered with opioid analgesics and sedative-hypnotics to the desired clinical response. Continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation. These cardiorespiratory effects may be more likely to occur in patients with obstructive sleep apnea, the elderly, and ASA III or IV patients.

Hypersensitivity Reactions
Byfavo contains dextran 40, which can cause hypersensitivity reactions, including rash, urticaria, pruritus, and anaphylaxis. Byfavo is contraindicated in patients with a history of severe hypersensitivity reaction to dextran 40 or products containing dextran 40.

Neonatal Sedation
Use of benzodiazepines during the later stages of pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) in the neonate. Observe newborns for signs of sedation and manage accordingly.

Pediatric Neurotoxicity
Published animal studies demonstrate that anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of this is not clear. However, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life but may extend out to approximately 3 years of age in humans.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

Adverse Reactions
The most common adverse reactions reported in >10% of patients (N=630) receiving Byfavo 5-30 mg (total dose) and undergoing colonoscopy (two studies) or bronchoscopy (one study) were: hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension.

Use in Specific Populations
Pregnancy
There are no data on the specific effects of Byfavo on pregnancy. Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to benzodiazepines during pregnancy and labor for signs of sedation and respiratory depression.

Lactation
Monitor infants exposed to Byfavo through breast milk for sedation, respiratory depression, and feeding problems. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 5 hours after Byfavo administration.

Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Byfavo should not be used in patients less than 18 years of age.

Geriatric Use
No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, there is a potential for greater sensitivity (eg, faster onset, oversedation, confusion) in some older individuals. Administer supplemental doses of Byfavo slowly to achieve the level of sedation required and monitor all patients closely for cardiorespiratory complications.

Hepatic Impairment
In patients with severe hepatic impairment, the dose of Byfavo should be carefully titrated to effect. Depending on the overall status of the patient, lower frequency of supplemental doses may be needed to achieve the level of sedation required for the procedure. All patients should be monitored for sedation-related cardiorespiratory complications.

Abuse and Dependence
Byfavo is a federally controlled substance (CIV) because it contains remimazolam which has the potential for abuse and physical dependence.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088

Please click to access full Prescribing Information.

BYF HCP ISI 10/2020

ASA=American Society of Anesthesiologists Physical Status. CYP450=cytochrome P450.

References: 1. Byfavo [package insert]. Indianapolis, IN: Acacia Pharma Inc. 2. Pambianco D, Cash B. New horizons for sedation: the ultrashort acting benzodiazepine remimazolam. Tech Gastrointest Endosc. 2016;18:22-28. 3. Rex DK, Bhandari R, Desta T, et al. A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy. Gastrointest Endosc. 2018;88(3):427-437. 4. Pastis NJ, Yarmus LB, Schippers F. Safety and efficacy of remimazolam compared with placebo and midazolam for moderate sedation during bronchoscopy. Chest. 2019;155(1);137-147. 5. Rex DK, Bhandari R, Lorch DG, et al. Safety and efficacy of remimazolam in high risk colonoscopy: a randomized trial. Dig Liver Dis. 2021;53(1):94-101.

INDICATION
PEMFEXY is indicated in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC).

PEMFEXY is indicated as a single agent for the maintenance treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

PEMFEXY is indicated as a single agent for the treatment of patients with recurrent, metastatic non-squamous non-small cell lung cancer (NSCLC) after prior chemotherapy.

Limitation of Use: PEMFEXY is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

PEMFEXY is indicated in combination with cisplatin for the initial treatment of patients with malignant pleural mesothelioma (MPM), whose disease is unresectable or who are otherwise not candidates for curative surgery.

CONTRAINDICATION
PEMFEXY is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

WARNINGS AND PRECAUTIONS

Myelosuppression and Increased Risk of Myelosuppression Without Vitamin Supplementation

PEMFEXY can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation.

7 Days prior to treatment with PEMFEXY, patients must be instructed to initiate supplementation with oral folic acid. Intramuscular injections of vitamin B 12  are also required 7 days prior to PEMFEXY treatment. Continue vitamin supplementation during treatment and for 21 days after the last dose of PEMFEXY to reduce the severity of treatment-related hematologic and gastrointestinal toxicities. Obtain a complete blood count at the beginning of each cycle. Do not administer PEMFEXY until the ANC is at least 1500 cells/mm 3 and platelet count is at least 100,000 cells/mm 3 . Permanently reduce PEMFEXY in patients with an ANC of less than 500 cells/mm 3 or platelet count of less than 50,000 cells/mm 3  in previous cycles.
In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the pemetrexed arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%.

Renal Failure
Pemetrexed can cause severe, and sometimes fatal, renal toxicity. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with PEMFEXY. The incidences of renal failure in clinical studies in which patients received pemetrexed with cisplatin were 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received pemetrexed as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI). Withhold PEMFEXY in patients with a creatinine clearance of less than 45 mL/min.

Bullous and Exfoliative Skin Toxicity
Serious and sometimes fatal, bullous, blistering, and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/toxic epidermal necrolysis, can occur with pemetrexed. Permanently discontinue PEMFEXY for severe and life-threatening bullous, blistering, or exfoliating skin toxicity.

Interstitial Pneumonitis
Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed. Withhold PEMFEXY for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue PEMFEXY.

Radiation Recall
Radiation recall can occur with pemetrexed in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue PEMFEXY for signs of radiation recall.

Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment
Exposure to pemetrexed is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of pemetrexed. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of PEMFEXY. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for pemetrexed adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity.

Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, PEMFEXY can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m 2 . Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with PEMFEXY and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMFEXY and for 3 months after the final dose.

DRUG INTERACTIONS
Ibuprofen increases exposure (AUC) of pemetrexed. In patients with creatinine clearance between 45 mL/min and 79 mL/min:

• Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of PEMFEXY.
• Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

ADVERSE REACTIONS
Severe adverse reactions (Grade 3-4) occurring in fully vitamin supplemented patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) receiving pemetrexed in combination with cisplatin versus gemcitabine in combination with cisplatin for initial treatment (JMDB),respectively, were neutropenia (15% vs 27%); fatigue (7% vs 5%); nausea (7% vs 4%); anemi(6% vs 10%); vomiting (6% vs 6%); thrombocytopenia (4% vs 13%); anorexia (2% vs 1%); diarrhea (1% vs 2%); elevated creatinine (1% vs 1%); stomatitis/pharyngitis (1% vs 0%); and constipation (1% vs 0%).

Common adverse reactions (all grades) occurring in ≥5% fully vitamin supplemented patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) receiving pemetrexed in combination with cisplatin versus gemcitabine in combination with cisplatin for initial treatment (JMDB), respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); elevated creatinine (10% vs 7%), sensory neuropathy (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); and dyspepsia/heartburn (5% vs 6%).

Severe adverse reactions (Grade 3-4) occurring in patients with non-progressive locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) receiving pemetrexed as a single agent versus placebo as maintenance treatment (JMEN), respectively, following non-pemetrexed containing, platinum-based induction therapy were fatigue (5% vs 1%); anemia (3% vs 1%); neutropenia (3% vs 0%); infection (2% vs 0%); anorexia (2% vs 0%); nausea (1% vs 1%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); and sensory neuropathy (1% vs 0%).

Common adverse reactions (all grades) occurring in ≥5% patients with non-progressive locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) receiving pemetrexed as a single agent versus placebo as maintenance treatment (JMEN), respectively, following non-pemetrexed containing, platinum-based induction therapy were fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); anemia (15% vs 6%); increased ALT (10% vs 4%); rash/desquamation (10% vs 3%); sensory neuropathy (9% vs 4%); vomiting (9% vs 1%); increased AST (8% vs 4%); mucositis/stomatitis (7% vs 2%); neutropenia (6% vs 0%); diarrhea (5% vs 3%); and infection (5% vs 2%).

Severe adverse reactions (Grade 3-4) occurring in patients with non-progressive locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) receiving pemetrexed as a single agent versus placebo as maintenance treatment (PARAMOUNT), respectively, following pemetrexed plus cisplatin induction therapy were anemia (4.8% vs 0.6%); fatigue (4.5% vs 0.6%); neutropenia (3.9% vs 0%); nausea (0.3% vs 0%); and mucositis/stomatitis (0.3% vs 0%).

Common adverse reactions (all grades) occurring in ≥5% patients with non-progressive locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) receiving pemetrexed as a single agent versus placebo as maintenance treatment (PARAMOUNT),respectively, following pemetrexed plus cisplatin induction therapy were fatigue (18% vs 11%); anemia (15% vs 4.8%); nausea (12% vs 2.4%); neutropenia (9% vs 0.6%); vomiting (6% vs 1.8%); edema (5% vs 3.6%); and mucositis/stomatitis (5% vs 2.4%).

Severe adverse reactions (Grade 3-4) occurring in fully supplemented patients with recurrent metastatic non-squamous non-small cell lung cancer (NSCLC) receiving pemetrexed as a single agent versus docetaxel as 2nd-line treatment after prior chemotherapy (JMEI), respectively, were
neutropenia (5% vs 40%); fatigue (5% vs 5%); anemia (4% vs 4%); nausea (3% vs 2%); anorexia (2% vs 3%); vomiting (2% vs 1%); thrombocytopenia (2% vs 0%); increased ALT (2% vs 0%); alopecia (1% vs 2%); stomatitis/pharyngitis (1% vs 1%); and increased AST (1% vs 0%).

Common adverse reactions (all grades) occurring in ≥5% of fully supplemented patients with recurrent metastatic non-squamous non-small cell lung cancer (NSCLC) receiving pemetrexed as a single agent versus docetaxel as 2nd-line treatment after prior chemotherapy (JMEI), respectively, were fatigue (34% vs 36%); nausea (31% vs 17%); anorexia (22% vs 24%); anemia (19% vs 22%); vomiting (16% vs 12%); stomatitis/pharyngitis (15% vs 17%); rash/desquamation (14% vs 6%); diarrhea (13% vs 24%); neutropenia (11% vs 45%); fever (8% vs 8%); thrombocytopenia (8% vs 1%); increased ALT (8% vs 1%); pruritus (7% vs 2%); increased AST (7% vs 1%); alopecia (6% vs 38%); and constipation (6% vs 4%).

Severe adverse reactions (Grade 3-4) occurring in fully supplemented subgroup of patients with malignant pleural mesothelioma (MPM) receiving pemetrexed in combination with cisplatin versus cisplatin alone (JMCH), respectively, were neutropenia (23% vs 3%); nausea (12% vs 6%); vomiting (11% vs 4%); fatigue (10% vs 9%); thrombocytopenia (5% vs 0%); dehydration (4% vs 1%); anemia (4% vs 0%); diarrhea (4% vs 0%); stomatitis/pharyngitis (3% vs 0%); decreased creatinine clearance (1% vs 2%); elevated creatinine (1% vs 1%); anorexia (1% vs 1%); constipation (1% vs 1%); dyspepsia (1% vs 0%); and rash (1% vs 0%).

Common adverse reactions (all grades) occurring in ≥5% of fully supplemented subgroup of patients with malignant pleural mesothelioma (MPM) receiving pemetrexed in combination with cisplatin versus cisplatin alone (JMCH), respectively, were nausea (82% vs 77%); vomiting (57% vs 50%); neutropenia (56% vs 13%); fatigue (48% vs 42%); anemia (26% vs 10%); thrombocytopenia (23% vs 9%); stomatitis/pharyngitis (23% vs 6%); anorexia (20% vs 14%); diarrhea (17% vs 8%); decreased creatinine clearance (16% vs 18%); rash (16% vs 5%); constipation (12% vs 7%); elevated creatinine (11% vs 10%); alopecia (11% vs 6%); sensory neuropathy (10% vs 10%); taste disturbance (8% vs 6%); dehydration (7% vs 1%); conjunctivitis (5% vs 1%); and dyspepsia (5% vs 1%).

USE IN SPECIFIC PATIENT POPULATIONS

Pregnancy
There are no available data on pemetrexed use in pregnant women. Based on findings from animal studies and its mechanism of action, PEMFEXY can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m 2. Advise pregnant women on the potential risk to a fetus.

Lactation
There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from PEMFEXY, advise women not to breastfeed during treatment with PEMFEXY and for one week after last dose.

Females and Males of Reproductive Potential
Verify pregnancy status of females of reproductive potential prior to initiating PEMFEXY. PEMFEXY can cause fetal harm when administered to a pregnant woman. Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with PEMFEXY and for 6 months after the final dose. Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with PEMFEXY and for 3 months after the final dose. PEMFEXY may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible.

Pediatric Use
The safety and effectiveness of PEMFEXY in pediatric patients have not been established. Adverse reactions observed in pediatric patients studied were similar to those observed in adults.

Geriatric Use
The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients in at least one of five randomized clinical trials.

Renal Impairment
PEMFEXY is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to pemetrexed compared with patients with normal renal function. No dosage is recommended for patients with creatinine clearance less than 45 mL/min.

For safety and dosing guidelines for PEMFEXY, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the full Prescribing Information.
To report SUSPECTED ADVERSE REACTIONS, contact Eagle Pharmaceuticals, Inc. at 1-855-318-2170 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Indications
BELRAPZO^® (bendamustine hydrochloride injection) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

BELRAPZO^® (bendamustine hydrochloride injection) is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

IMPORTANT SAFETY INFORMATION
Contraindications: BELRAPZO^® is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol. Reactions to bendamustine HCl have included anaphylaxis and anaphylactoid reactions.

Myelosuppression: Bendamustine HCl caused severe myelosuppression (Grade 3-4) in 98% of patients in the 2 NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the absolute neutrophil count (ANC) should be ≥1 x 109/L and the platelet count should be ≥75 x 109/L.

Infections: Infection, including pneumonia, sepsis, septic shock, hepatitis, and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports for bendamustine HCl. Patients with myelosuppression following treatment with bendamustine HCl are more susceptible to infections. Advise patients with myelosuppression following BELRAPZO^® treatment to contact a physician immediately if they have symptoms or signs of infection. Patients treated with bendamustine HCl are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Patients should undergo appropriate measures (including clinical and laboratory monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to administration.

Anaphylaxis and Infusion Reactions: Infusion reactions to bendamustine HCl have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue BELRAPZO^® for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering individual benefits, risks, and supportive care.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with bendamustine HCl has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of bendamustine HCl and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of bendamustine HCl therapy. However, there may be an increased risk of severe skin toxicity when bendamustine HCl and allopurinol are administered concomitantly.

Skin Reactions: Fatal and serious skin reactions have been reported with bendamustine HCl treatment in clinical trials and postmarketing safety reports, including toxic skin reactions [Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)], bullous exanthema, and rash. Events occurred when bendamustine HCl was given as a single agent and in combination with other anticancer agents or allopurinol.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold, or discontinue BELRAPZO^®.

Hepatotoxicity: Fatal and serious cases of liver injury have been reported with bendamustine HCl. Combination therapy, progressive disease, or reactivation of hepatitis B were confounding factors in some patients. Most cases were reported within the first 3 months of starting therapy. Monitor liver chemistry tests prior to and during BELRAPZO^® therapy.

Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine HCl, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma.

Extravasation Injury: Bendamustine HCl extravasations resulting in hospitalizations from erythema, marked swelling, and pain has been reported in postmarketing. Ensure good venous access prior to starting BELRAPZO^® infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of BELRAPZO^®.

Embryo-fetal Toxicity: Bendamustine HCl can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. Advise women to avoid becoming pregnant while using BELRAPZO^®.

Most Common Adverse Reactions

• Most common non-hematologic adverse reactions for CLL (frequency ≥ 15%) are pyrexia, nausea, and vomiting.
• Most common non-hematologic adverse reactions for NHL (frequency ≥ 15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis.
• Most common hematologic abnormalities (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia.

TO REPORT ADVERSE REACTIONS, contact Eagle Pharmaceuticals, Inc. at 1-855-318-2170 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.

Indications
RYANODEX^® (dantrolene sodium) for injectable suspension is indicated for the treatment of malignant hyperthermia in conjunction with appropriate supportive measures, and for the prevention of malignant hyperthermia in patients at high risk.

Important Safety Information
RYANODEX^® is not a substitute for appropriate supportive measures in the treatment of malignant hyperthermia (MH), including discontinuing use of MH-triggering anesthetic agents, managing the metabolic acidosis, instituting cooling when necessary, and administering diuretics to prevent late kidney injury due to myoglobinuria (the amount of mannitol in RYANODEX® is insufficient to maintain diuresis).

RYANODEX^® is associated with skeletal muscle weakness such as loss of grip strength and weakness in the legs, as well as drowsiness, dizziness, dysphagia, dyspnea, and decreased inspiratory capacity. Patients should not be permitted to ambulate without assistance until they have normal strength and balance. Care must be taken to prevent extravasation of RYANODEX® into the surrounding tissue due to the high pH of the reconstituted RYANODEX^® suspension and potential for tissue necrosis.

Indications
BENDEKA^® is indicated for the treatment of patients with Chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Important Safety Information
Contraindication: BENDEKA^® (bendamustine HCI) injection is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine HCl, polyethylene glycol 400, propylene glycol, or monothioglycerol.

Myelosuppression: Bendamustine HCl caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. Monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle.

Infections: Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred. Patients with myelosuppression following treatment with BENDEKA^® are more susceptible to infections. Patients treated with bendamustine HCl are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Patients should undergo appropriate monitoring, prophylaxis, and treatment measures prior to administration.

Anaphylaxis and Infusion Reactions: Infusion reactions to bendamustine HCl have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with bendamustine HCl has occurred. The onset tends to be within the first treatment cycle with bendamustine HCl and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when bendamustine HCl and allopurinol are administered concomitantly.

Skin Reactions: Fatal and serious skin reactions have been reported with bendamustine HCl and include, toxic skin reactions, [Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)], bullous exanthema and rash. Events occurred when bendamustine HCl was given as a single agent and in combination with other anticancer agents or allopurinol. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold, or discontinue BENDEKA^®.

Hepatotoxicity: Fatal and serious cases of liver injury have been reported with bendamustine HCl. Combination therapy, progressive disease, or reactivation of hepatitis B were confounding factors in some patients. Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during BENDEKA^® therapy.

Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine HCl, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with BENDEKA^® has not been determined.

Extravasation Injury: Bendamustine HCl extravasations have been reported in post-marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting BENDEKA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of BENDEKA^®.

Embryo-fetal Toxicity: Bendamustine HCl can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using BENDEKA^®.

Most Common Adverse Reactions:
Adverse reactions (frequency >5%) during infusion and within 24 hours post-infusion are nausea and fatigue.
The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting.
The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis.
The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia.

INDICATION
Vasopressin Injection is indicated to increase blood pressure in adults with vasodilatory shock who remain hypotensive despite fluids and catecholamines.

CONTRAINDICATION
Vasopressin Injection is contraindicated in patients with known allergy or hypersensitivity to 8-L-arginine vasopressin or chlorobutanol.

WARNINGS AND PRECAUTIONS

Worsening Cardiac Functions
A decrease in cardiac index may be observed with the use of vasopressin.

Reversible Diabetes Insipidus
Patients may experience reversible diabetes insipidus, manifested by the development of polyuria, a diluted urine and hypernatremia, after cessation of treatment with vasopressin. Monitor serum electrolytes, fluid status and urine output after vasopressin discontinuation. Some patients may require readministration of vasopressin or administration of desmopressin to correct fluid and electrolyte shifts.

DRUG INTERACTIONS

Catecholamines
Use with catecholamines is expected to result in an additive effect on mean arterial blood pressure and other hemodynamic parameters. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.

Indomethacin
Use with indomethacin may prolong the effect of Vasopressin Injection on cardiac index and systemic vascular resistance. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.

Ganglionic Blocking Agents
Use with ganglionic blocking agents may increase the effect of Vasopressin Injection on mean arterial blood pressure. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.

Drugs Suspected of Causing Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Use with drugs suspected of causing SIADH (e.g., SSRIs, tricyclic antidepressants, haloperidol, chlorpropamide, enalapril, methyldopa, pentamidine, vincristine, cyclophosphamide, ifosfamide, felbamate) may increase the pressor effect in addition to the antidiuretic effect of Vasopressin Injection. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.

Drugs Suspected of Causing Diabetes Insipidus
Use with drugs suspected of causing diabetes insipidus (e.g., demeclocycline, lithium, foscarnet, clozapine) may decrease the pressor effect in addition to the antidiuretic effect of Vasopressin Injection. Hemodynamic monitoring is recommended; adjust the dose of vasopressin as needed.

ADVERSE REACTIONS
Adverse reactions associated with the use of vasopressin were identified in the literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

The most common adverse reactions associated with the use of vasopressin include decreased cardiac output, bradycardia, tachyarrhythmias, hyponatremia and ischemia (coronary, mesenteric, skin, digital).

USE IN SPECIFIC PATIENT POPULATIONS

Pregnancy
There are no available data on Vasopressin Injection use in pregnant women to inform a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted. Because of increased clearance of vasopressin in the second and third trimester, the dose of Vasopressin Injection may need to be increased.

Vasopressin Injection may produce tonic uterine contractions that could threaten the continuation of pregnancy.

Lactation
There are no data on the presence of vasopressin injection in either human or animal milk, the effects on the breastfed infant, or the effects on milk production.

Pediatric Use
Safety and effectiveness of Vasopressin Injection in pediatric patients with vasodilatory shock have not been established.

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

For safety and dosing guidelines for Vasopressin Injection, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the full Prescribing Information.

TO REPORT SUSPECTED ADVERSE REACTIONS, contact Eagle Pharmaceuticals, Inc. at 1-855-318-2170 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.