Vials and Other Injectable Medications

BREVIBLOC (esmolol hydrochloride) Injection

2500 mg / 250 mL (10 mg/mL) Ready-to-use INTRAVIA Bags

2000 mg / 100 mL (20 mg/mL) Ready-to-use INTRAVIA Bags

Indications and Important Risk Information

Indications

BREVIBLOC injection is a beta adrenergic blocker indicated for the short-term treatment of:

• Control of ventricular rate in supraventricular tachycardia including atrial fibrillation and atrial flutter and control of heart rate in noncompensatory sinus tachycardia
• Control of perioperative tachycardia and hypertension

Important Risk Information

• Contraindications:
• Severe sinus bradycardia
• Heart block greater than first degree
• Sick sinus syndrome
• Decompensated heart failure
• Cardiogenic shock
• IV administration of cardiodepressant calcium-channel antagonists (e.g., verapamil) and BREVIBLOC injection in close proximity; fatal cardiac arrests have occurred
• Pulmonary hypertension
• Hypersensitivity reactions, including anaphylaxis, to esmolol or any of the inactive ingredients of the product
• Hypotension: Hypotension can occur at any dose but is dose-related. Patients with hemodynamic compromise or on interacting medications are at particular risk. Severe reactions may include loss of consciousness, cardiac arrest, and death. Monitor patients closely, especially if pretreatment blood pressure is low. In case of an unacceptable drop in blood pressure, reduce or stop BREVIBLOC injection. Decrease of dose or termination of infusion reverses hypotension, usually within 30 minutes. 
• Bradycardia: Bradycardia, including sinus pause, heart block, severe bradycardia, and cardiac arrest have occurred. Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders may be at increased risk. Monitor heart rate and rhythm. If severe bradycardia develops, reduce or stop BREVIBLOC injection. 
• Cardiac Failure: Beta blockers, like BREVIBLOC injection, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. At the first sign or symptom of impending cardiac failure, stop BREVIBLOC injection and start supportive therapy.
• Reactive Airways Disease: Patients with reactive airways disease should, in general, not receive beta blockers. Titrate BREVIBLOC Injection to the lowest possible effective dose. Stop infusion immediately in the event of a bronchospasm.
• Hypoglycemia: Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting.
• Use in Patients with Pheochromocytoma: Risk of unopposed alpha-agonism and severe hypertension in untreated pheochromocytoma. If used in the setting of pheochromocytoma, give it in combination with an alpha-blocker, and only after the alpha-blocker has been initiated.
• Use in Hypovolemic Patients: In hypovolemic patients, BREVIBLOC injection can attenuate reflex tachycardia and increase the risk of hypotension.
• Abrupt Discontinuation of BREVIBLOC Injection: Severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias have been reported in patients with coronary artery disease upon abrupt discontinuation of beta blocker therapy. Observe patients for signs of myocardial ischemia when discontinuing BREVIBLOC injection.
• Adverse Reactions: Most common adverse reactions (incidence >10%) are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension.
• Drug Interactions:
  • Digitalis glycosides: Risk of bradycardia
  • Anticholinesterases: Prolongs neuromuscular blockade
  • Antihypertensive agents: Risk of rebound hypertension
  • Sympathomimetic drugs: Dose adjustment needed
  • Vasoconstrictive and positive inotropic effect substances: Avoid concomitant use

Please see accompanying full Prescribing Information for BREVIBLOC (esmolol hydrochloride) Injection.

Cyclophosphamide for Injection, USP

Indications and Important Risk Information

Indications

• Malignant Diseases : Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs.
• Cyclophosphamide is indicated for the treatment of: Malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma. Multiple myeloma. Leukemias: Chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia (cyclophosphamide given during remission is effective in prolonging its duration). Mycosis fungoides (advanced disease). Neuroblastoma (disseminated disease). Adenocarcinoma of the ovary. Retinoblastoma. Carcinoma of the breast.
• Minimal Change Nephrotic Syndrome in Pediatric Patients:
  Cyclophosphamide is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatrics patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.
  Limitations of Use:
  The safety and effectiveness for the treatment of nephrotic syndrome in adults or other renal disease has not been established.

IMPORTANT RISK INFORMATION:

• Cyclophosphamide is contraindicated in patients who have demonstrated a previous hypersensitivity to it. Anaphylactic reactions including death have been reported with cyclophosphamide. Possible cross-sensitivity with other alkylating agents can occur.
• Cyclophosphamide is contraindicated in patients with urinary outflow obstruction.
• Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock. Latent infections can be reactivated. Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide should not be administered to patients with neutrophils ≤1,500/mm³ and platelets<50,000/mm³.
• Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Discontinue cyclophosphamide therapy in case of severe hemorrhagic cystitis. Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of cyclophosphamide treatment or cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or long-term use of cyclophosphamide. Cyclophosphamide should be used with caution, if at all, in patients with active urinary tract infection.
• Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure, which may be fatal, have been reported with cyclophosphamide therapy. Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with regimens that included cyclophosphamide. The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in patients with advanced age, and in patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other cardiotoxic agents. Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease.
• Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Late onset pneumonitis (greater than 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis may develop years after treatment with cyclophosphamide. Monitor patients for signs and symptoms of pulmonary toxicity.
• Cyclophosphamide is genotoxic. Secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in patients treated with cyclophosphamide-containing regimens.
• Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide-containing regimens.
• Cyclophosphamide can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception during treatment and for up to 1 year after completion of therapy.
• Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause irreversible sterility in some patients. Advise patients on the potential risks for infertility.
• Cyclophosphamide may interfere with normal wound healing.
• Hyponatremia associated with increased total body water, acute water intoxication, and a syndrome resembling SIADH (syndrome of inappropriate secretion of antidiuretic hormone), which may be fatal, has been reported.
• Common Adverse Reactions include: Neutropenia, also, fever without documented infection has been reported in neutropenic patients. Nausea and vomiting, anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. Alopecia occurs in patients treated with cyclophosphamide. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur.

Please see accompanying full Prescribing Information for Cyclophosphamide for Injection, USP.

Bendamustine Hydrochloride Injection

100 mg/4 mL (25 mg/mL) Multiple-Dose Vial

Indications and Important Risk Information

Indications

Bendamustine Hydrochloride Injection is an alkylating drug indicated for treatment of adult 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 six months of treatment with rituximab or a rituximab-containing regimen.

Important Risk Information

Contraindications

Bendamustine Hydrochloride Injection is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, alcohol, or monothioglycerol.

Warnings and Precautions

• Myelosuppression: Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. Bendamustine Hydrochloride Injection causes myelosuppression. Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Hematologic nadirs were observed predominantly in the third week of therapy. 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 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 hydrochloride. Patients with myelosuppression following treatment are more susceptible to infections; advise patients to contact a physician immediately if they have symptoms or signs of infection. Patients 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 for infection and infection reactivation prior to administration.
• Progressive Multifocal Leukoencephalopathy (PML): PML, including fatal cases, have occurred following treatment with bendamustine, primarily in combination with rituximab or obinutuzumab. Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected, withhold Bendamustine Hydrochloride Injection treatment and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.
• Anaphylaxis and Infusion Reactions: Infusion reactions to bendamustine hydrochloride 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. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue Bendamustine Hydrochloride Injection for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate.
• Tumor Lysis Syndrome: Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle 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 hydrochloride therapy. However, there may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly.
• Skin Reactions: Fatal and serious skin reactions have been reported with bendamustine hydrochloride 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 hydrochloride 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 Bendamustine Hydrochloride Injection.
• Hepatotoxicity: Fatal and serious cases of liver injury have been reported with Bendamustine Hydrochloride Injection. 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 therapy.
• Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine hydrochloride. Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment.
• Extravasation Injury: Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration.
• Embryo-Fetal Toxicity: Based on findings from animal reproduction studies and the drug’s mechanism of action, Bendamustine Hydrochloride Injection can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose.
• Adverse Reactions:
  •  Adverse reactions (frequency >5%) during infusion and within 24 hours post-infusion are nausea and fatigue.
  • Most common adverse reactions (≥15%) for CLL are anemia, thrombocytopenia, neutropenia, lymphopenia, leukopenia, hyperbilirubinemia, pyrexia, nausea, vomiting.
  • Most common adverse reactions (≥15%) for NHL are lymphopenia, leukopenia, anemia neutropenia, thrombocytopenia, nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis.
• Drug Interactions:
  • CYP1A2 Inhibitors: The coadministration with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with Bendamustine hydrochloride Injection. Consider alternative therapies that are not CYP1A2 inhibitors during treatment.
  • CYP1A2 Inducers: The coadministration with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of Bendamustine Hydrochloride Injection. Consider alternative therapies that are not CYP1A2 inducers during treatment.
• Use in Specific Populations:
  • Infertility: Based on findings from clinical studies and animal studies, Bendamustine Hydrochloride Injection may impair male fertility.
  • Renal Impairment: Do not use Bendamustine Hydrochloride Injection in patients with creatinine clearance (CLcr) < 30 mL/min.
  • Hepatic Impairment: Do not use Bendamustine Hydrochloride Injection in patients with AST or ALT 2.5-10 × upper limit of normal (ULN) and total bilirubin 1.5-3 × ULN, or total bilirubin > 3 × ULN.

Please see accompanying full Prescribing Information for Bendamustine Hydrochloride Injection.

Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection

200 mcg/50 mL (4 mcg/mL) in a 50 mL Galaxy container

400 mcg/100 mL (4 mcg/mL) in a 100 mL Galaxy container

Indications and Important Risk Information

Indications

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is an alpha₂-adrenergic receptor agonist indicated for:

• Sedation of initially intubated and mechanically ventilated adult patients during treatment in an intensive care setting. Administer dexmedetomidine hydrochloride in 0.9% sodium chloride injection by continuous infusion not to exceed 24 hours.
• Sedation of non-intubated adult patients prior to and/or during surgical and other procedures.

Important Risk Information

• Contraindications: None 
• Monitoring: Dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be administered only by persons skilled in the management of patients in the intensive care or operating room setting. Patients should be continuously monitored.
• Hypotension, Bradycardia, and Sinus Arrest: Clinically significant episodes of bradycardia and sinus arrest have been reported with administration in young, healthy adult volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration.
  Reports of hypotension and bradycardia have been associated with dexmedetomidine hydrochloride in 0.9% sodium chloride injection infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents.
  Caution should be exercised when administering to patients with advanced heart block and/or severe ventricular dysfunction. Hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients.
  Use with caution with co-administration with other vasodilators or negative chronotropic agents.
• Transient Hypertension: Has been observed primarily during the loading dose. Treatment has generally not been necessary, although reduction of the loading infusion rate may be desirable.
• Arousability: Some patients have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms.
• Tolerance and Tachyphylaxis: Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions.
• Hyperthermia or Pyrexia: May be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes.
• Hepatic Impairment: Clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function.
• Adverse Reactions: 
  • The most common adverse reactions (incidence >2%) in adults are hypotension, bradycardia, and dry mouth. 
  • Adverse reactions in adults, associated with infusions >24 hours in duration include ARDS, respiratory failure, and agitation.
• Drug Interactions: 
  • Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine hydrochloride in 0.9% sodium chloride injection or the concomitant medication may be required.

Please see accompanying full Prescribing Information for Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection.

Nitroglycerin in 5% Dextrose Injection

25 mg Nitroglycerin in 250 mL

50 mg Nitroglycerin in 250 mL

100 mg Nitroglycerin in 250 mL

Indications and Important Risk Information

Indications

• Nitroglycerin in 5% Dextrose Injection is indicated for treatment of peri-operative hypertension; for control of heart failure in the setting of acute myocardial infarction; for treatment of angina pectoris in patients who have not responded to sublingual nitroglycerin and ß-blockers; and for induction of intraoperative hypotension.

Important Risk Information

• Contraindications: Nitroglycerin in 5% Dextrose Injection is contraindicated in patients who are allergic to it. In patients with pericardial tamponade, restrictive cardiomyopathy, or constrictive pericarditis, cardiac output is dependent upon venous return. Intravenous nitroglycerin is contraindicated in patients with these conditions. Nitroglycerin is also contraindicated in patients with increased intracranial pressure. Do not use Nitroglycerin in 5% Dextrose Injection in patients who are taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors) such as sildenafil, tadalafil, or vardenafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia. Do not use Nitroglycerin in 5% Dextrose Injection in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.
• PVC Tubing: Use of PVC (polyvinyl chloride) tubing in infusion sets may lead to loss of active ingredient due to adsorption of nitroglycerin to PVC tubing, therefore dosage is affected. Nitroglycerin adsorption by PVC tubing is increased when the tubing is long, the flow rates are low, and the nitroglycerin concentration of the solution is high. Some in-line intravenous filters also adsorb nitroglycerin; these filters should be avoided.
• Severe Hypotension and Shock: Severe hypotension and shock may occur with even small doses of nitroglycerin. Monitor patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris.
• Angina: Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy. Tolerance development and occurrence of cross tolerance to other nitro compounds have been reported. In industrial workers who have long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence.
• Adverse Reactions: Adverse reactions to nitroglycerin are generally dose-related and almost all of these reactions are the result of nitroglycerin’s activity as a vasodilator. Headache, which may be severe, is the most commonly reported side effect. Transient episodes of lightheadedness may also occur.
• Drug Interactions: (not already described in the Contraindications section)
  • The vasodilating effects of nitroglycerin may be additive with those of antihypertensives (e.g., beta-blockers, calcium channel blockers and tricyclic antidepressants) and may cause increased hypotensive effects.
  • Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination.
  • Nitroglycerin at higher dosages may interfere with the anticoagulant effect of heparin. Intravenous nitroglycerin can induce heparin resistance.
  • Administration of Nitroglycerin in 5% Dextrose Injection through the same infusion set as blood can result in pseudoagglutination and hemolysis. Do not mix Nitroglycerin in 5% Dextrose Injection with any other medication of any kind.

Please see accompanying full Prescribing Information for Nitroglycerin in 5% Dextrose Injection.

Labetalol Hydrochloride Injection, USP

20 mg/4 mL (5 mg/mL) Single-dose Vial

100 mg/20 mL (5 mg/mL) Multi-dose Vial

200 mg/40 mL (5 mg/mL) Multi-dose Vial

Indications and Important Risk Information

Indications

Labetalol hydrochloride injection is indicated for control of blood pressure in severe hypertension.

Important Risk Information

Contraindications

Labetalol hydrochloride injection is contraindicated in bronchial asthma, overt cardiac failure, greater than first degree heart block, cardiogenic shock, severe bradycardia, other conditions associated with severe and prolonged hypotension, and in patients with a history of hypersensitivity to any component of the product.

Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with a history of obstructive airway disease, including asthma.

Warnings and Precautions

• Hepatic Injury: Severe hepatocellular injury, confirmed by rechallenge in at least one case, occurs rarely with labetalol therapy. The hepatic injury is usually reversible, but hepatic necrosis and death have been reported. Injury has occurred after both short- and long-term treatment and may be slowly progressive despite minimal symptomatology. Similar hepatic events have been reported with a related compound, dilevalol hydrochloride, including two deaths. Thus, for patients taking labetalol, periodic determination of suitable hepatic laboratory tests would be appropriate. Laboratory testing should also be done at the very first symptom or sign of liver dysfunction. If the patient has jaundice or laboratory evidence of liver injury, labetalol should be stopped and not restarted.
• Cardiac Failure: Although beta-blockers should be avoided in overt congestive heart failure, if necessary, labetalol can be used with caution in patients with a history of heart failure who are well compensated. Congestive heart failure has been observed in patients receiving labetalol. Labetalol does not abolish the inotropic action of digitalis on heart muscle.
• In Patients Without a History of Cardiac Failure: In patients with latent cardiac insufficiency, continued depression of the myocardium with beta-blocking agents over a period of time can lead, in some cases, to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or be given a diuretic, and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic, labetalol therapy should be withdrawn (gradually if possible).
• Ischemic Heart Disease: Angina pectoris has not been reported upon labetalol discontinuation. However, following abrupt cessation of therapy with some beta-blocking agents in patients with coronary artery disease, exacerbations of angina pectoris and, in some cases, myocardial infarction have been reported. Even in the absence of overt angina pectoris, when discontinuation of labetalol is planned, the patient should be carefully observed and should be advised to limit physical activity. If angina markedly worsens or acute coronary insufficiency develops, labetalol administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken.
• Nonallergic Bronchospasm (e.g., chronic bronchitis and emphysema): Since labetalol injection at the usual intravenous therapeutic doses has not been studied in patients with nonallergic bronchospastic disease, it should not be used in such patients.
• Pheochromocytoma: Intravenous labetalol has been shown to be effective in lowering the blood pressure and relieving symptoms in patients with pheochromocytoma; higher than usual doses may be required. However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol to patients with pheochromocytoma.
• Diabetes Mellitus and Hypoglycemia: Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; it may therefore be necessary to adjust the dose of antidiabetic drugs.
• Major Surgery: The necessity or desirability of withdrawing beta-blocking therapy prior to major surgery is controversial. Protracted severe hypotension and difficulty in restarting or maintaining a heartbeat have been reported with beta-blockers. The effect of labetalol’s alpha-adrenergic activity has not been evaluated in this setting. Several deaths have occurred when labetalol injection was used during surgery (including when used in cases to control bleeding).
• Rapid Decreases of Blood Pressure: Caution must be observed when reducing severely elevated blood pressure. Although such findings have not been reported with intravenous labetalol, a number of adverse reactions, including cerebral infarction, optic nerve infarction, angina, and ischemic changes in the electrocardiogram, have been reported with other agents when severely elevated blood pressure was reduced over time courses of several hours to as long as 1 or 2 days. The desired blood pressure lowering should therefore be achieved over as long a period of time as is compatible with the patient’s status.
• Adverse Reactions: Symptomatic postural hypotension (incidence 58%) is likely to occur if patients are tilted or allowed to assume the upright position within 3 hours of receiving labetalol injection. In U.S. clinical trials, the most common adverse reactions for labetalol injection were nausea, dizziness, transient increases in blood urea nitrogen and serum creatinine levels, and tingling of the scalp/skin.
• Drug Interactions:
• Drugs possessing beta-blocking properties can blunt the bronchodilator effect of beta-receptor agonist drugs in patients with bronchospasm; therefore, doses greater than the normal anti-asthmatic dose of beta-agonist bronchodilator drugs may be required.
• Synergism has been shown between halothane anesthesia and intravenously administered labetalol. During controlled hypotensive anesthesia using labetalol in association with halothane, high concentrations (3% or above) of halothane should not be used because the degree of hypotension will be increased and because of the possibility of a large reduction in cardiac output and an increase in central venous pressure. The anesthesiologist should be informed when a patient is receiving labetalol.
• Labetalol blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol hydrochloride is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur.
• Care should be taken if labetalol is used concomitantly with calcium antagonists of the verapamil type.
• When drug products that are alkaline, such as furosemide, have been administered in combination with labetalol, a white precipitate has been noted. Therefore, these drugs should not be administered in the same infusion line.

Please see accompanying full Prescribing Information for Labetalol Hydrochloride Injection, USP.

Naloxone Hydrochloride Injection, USP

[0.4 mg/mL 1 mL Single-Dose Vial and 4 mg/10 mL (0.4 mg/mL) 10 mL Multiple-Dose Vial]

Indications and Important Risk Information

Indications

Naloxone hydrochloride injection is indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids, including propoxyphene, methadone and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol, and cyclazocine.
Naloxone hydrochloride injection is also indicated for diagnosis of suspected or known acute opioid overdosage. Naloxone hydrochloride injection may be useful as an adjunctive agent to increase blood pressure in the management of septic shock.

Important Risk Information

Contraindications

Naloxone hydrochloride injection is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients contained in the formulation.

Warnings and Precautions

• Drug Dependence: Naloxone hydrochloride injection should be administered cautiously to persons including newborns of mothers who are known or suspected to be physically dependent on opioids. In such cases an abrupt and complete reversal of opioid effects may precipitate an acute withdrawal syndrome. The signs and symptoms of opioid withdrawal in a patient physically dependent on opioids may include, but are not limited to, the following: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In the neonate, opioid withdrawal may also include: convulsions, excessive crying, and hyperactive reflexes.
• Repeat Administration: The patient who has satisfactorily responded to naloxone hydrochloride should be kept under continued surveillance and repeated doses of naloxone hydrochloride should be administered, as necessary, since the duration of action of some opioids may exceed that of naloxone hydrochloride.
• Respiratory Depression due to Other Drugs: Naloxone hydrochloride is not effective against respiratory depression due to non-opioid drugs and in the management of acute toxicity caused by levopropoxyphene. Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete or require higher doses of naloxone. If an incomplete response occurs, respirations should be mechanically assisted as clinically indicated.
• General: In addition to naloxone hydrochloride, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning. Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone hydrochloride in postoperative patients may result in significant reversal of analgesia and may cause agitation.
• General: Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had pre-existing cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone hydrochloride should be used with caution in patients with preexisting cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema.
• Pediatric Use: Naloxone hydrochloride injection may be administered intravenously, intramuscularly or subcutaneously in children and neonates to reverse the effects of opiates. Although the opiate-intoxicated child responds dramatically to naloxone hydrochloride, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized.
• Adverse Reactions:
• Adverse events associated with the postoperative use of naloxone hydrochloride are listed by organ system and in decreasing order of frequency as follows:
  Cardiac Disorders: pulmonary edema, cardiac arrest or failure, tachycardia, ventricular fibrillation, and ventricular tachycardia. Death, coma, and encephalopathy have been reported as sequelae of these events.
  Gastrointestinal Disorders: vomiting, nausea
  Nervous System Disorders: convulsions, paraesthesia, grand mal convulsion
  Psychiatric Disorders: agitation, hallucination, tremulousness
  Respiratory, Thoracic and Mediastinal Disorders: dyspnea, respiratory depression, hypoxia
  Skin and Subcutaneous Tissue Disorders: nonspecific injection site reactions, sweating
  Vascular Disorders: hypertension, hypotension, hot flushes or flushing.
• Drug Interactions: Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts.

Please see accompanying full Prescribing Information for Naloxone Hydrochloride Injection, USP, Single-Dose Vial and Naloxone Hydrochloride Injection, USP, Multiple-Dose Vial.

DOXIL (doxorubicin HCl liposome injection)

Important Risk Information

INDICATIONS

DOXIL® liposomal infusion is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

DOXIL® liposomal infusion is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

DOXIL® liposomal infusion, in combination with bortezomib, is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

IMPORTANT RISK INFORMATION

WARNING: CARDIOMYOPATHY and INFUSION-RELATED REACTIONS DOXIL liposomal infusion can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2 to 550 mg/m2. Assess left ventricular cardiac function prior to initiation of DOXIL liposomal infusion and during and after treatment. See additional information on Cardiomyopathy in Warnings and Precautions below. Serious, life-threatening, and fatal infusion-related reactions can occur with DOXIL liposomal infusion. Acute infusion-related reactions occurred in 11% of patients with solid tumors. Withhold DOXIL liposomal infusion for infusion-related reactions and resume at a reduced rate. Discontinue DOXIL liposomal infusion for serious or life-threatening infusion-related reactions. See additional information on Cardiomyopathy in Warnings and Precautions below.

 

Dosage and Administration - Important Use Information

Do not substitute DOXIL liposomal infusion for other doxorubicin hydrochloride products. Do not administer as an undiluted suspension or as an intravenous bolus.

Contraindications

DOXIL liposomal infusion is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin hydrochloride.

Warnings and Precautions

Cardiomyopathy: Doxorubicin hydrochloride can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin hydrochloride is generally proportional to the cumulative exposure. Administer DOXIL liposomal infusion to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

Infusion-Related Reactions: Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with DOXIL liposomal infusion: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension.

Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative equipment are available for immediate use prior to initiation of DOXIL liposomal infusion.

Discontinue DOXIL liposomal infusion for serious or life-threatening infusion-related reactions.

Hand-Foot Syndrome (HFS) may occur.

• HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier.
• Delay DOXIL liposomal infusion for the first episode of Grade 2 or greater HFS
• Dose Modification or discontinue DOXIL liposomal infusion if HFS is severe and debilitating

Secondary Oral Neoplasms: Secondary oral cancers, primarily squamous cell carcinoma, have been reported from post-marketing experience in patients with long-term (more than one year) exposure to DOXIL liposomal infusion. These malignancies were diagnosed both during treatment with DOXIL liposomal infusion and up to 6 years after the last dose. Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer.

Embryo-Fetal Toxicity: Based on animal data, DOXIL liposomal infusion can cause fetal harm when administered to a pregnant woman; avoid the use of DOXIL liposomal infusion during the 1st trimester. Advise pregnant women of the potential risk to a fetus.

Females and males of reproductive potential to use effective contraception during and for 6 months after treatment with DOXIL liposomal infusion.

Use in Specific Populations

Lactation: because of the potential for serious adverse reactions in breastfed infants from DOXIL liposomal infusion, discontinue breastfeeding during treatment with DOXIL liposomal infusion.

Adverse Reactions

Most common adverse reactions (>20%) are asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, thrombocytopenia, and anemia.

Please see accompanying full Prescribing Information, including BOXED WARNINGS for DOXIL (doxorubicin HCl liposome injection)