Aldesleukin

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: 125-l-Serine-2-133-Interleukin 2 (human reduced)
Molecular Formula: C₆₉₀H₁₁₁₅N₁₇₇O₂₀₃S₆
CAS Number: 110942-02-4
Brands: Proleukin

• Cardiac and Pulmonary Function


• 
  

  Use only in patients with normal cardiac and pulmonary function as defined by thallium stress testing and pulmonary function tests.¹ Use with extreme caution in patients with histories of cardiac or pulmonary disease even if thallium stress and pulmonary function test results are normal.¹ (See Toxicity and Adequate Patient Monitoring under Cautions.)

  
  

• Experience of Supervising Clinician


• 
  

  Use in hospital setting under supervision of a qualified clinician experienced in therapy with antineoplastic agents.¹ Use only when an intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine are available in case aldesleukin-induced toxicities develop.¹

  
  

• Capillary Leak Syndrome


• 
  

  Risk of developing capillary leak syndrome (CLS); characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into extravascular space.¹ Results in hypotension and reduced organ perfusion; may be severe or fatal.¹ CLS may be associated with cardiac arrhythmias (supraventricular and ventricular), angina, MI, respiratory insufficiency requiring intubation, GI bleeding or infarction, renal insufficiency, edema, and mental status changes.¹ (See Capillary Leak Syndrome under Cautions.)

  
  

• Infections


• 
  

  Possible impaired neutrophil function (reduced chemotaxis) and increased risk of disseminated infection, including sepsis and bacterial endocarditis.¹ Treat preexisting bacterial infections prior to initiation of therapy.¹ Patients with indwelling central lines are at a higher risk for gram-positive bacterial infections.^{1 6 15} Prophylaxis with oxacillin, nafcillin, ciprofloxacin, or vancomycin associated with a reduced incidence of staphylococcal infections.¹

  
  

• CNS Effects


• 
  

  Withhold administration if moderate-to-severe lethargy or somnolence develops; continued administration may result in coma.¹ (See CNS Effects under Cautions.)

  
  

Introduction

Antineoplastic and immunomodulating agent; human interleukin-2 (IL-2) derivative and biosynthetic (recombinant DNA origin) cytokine (i.e., lymphokine).^{1 2}

Uses for Aldesleukin

Renal Cell Cancer

Treatment of metastatic renal cell carcinoma in selected patients, alone^{1 22 109 111 116 117 144} or in combination^{1 5 22} with surgery¹⁴⁴ or other drug therapies, such as biologic response modifiers (e.g., interferon alfa), ^{37 42 43 44 45 46 49 53 115 117 119 120 121 122 123 124 125 126 136 138 161} or adoptive immunotherapy (e.g., lymphokine-activated killer [LAK] cells, tumor-infiltrating lymphocytes [TILs]).^{26 27 29 30 31 32 37 38 47 48 49 51 98 105 127 128 156}

There is no generally accepted standard therapy for metastatic renal cell carcinoma.^{22 52 64 109}

Despite initial response to aldesleukin, tumor relapse is common, particularly following partial response.¹¹³ Treatment of relapsed disease with the same aldesleukin-based therapy is rarely effective,^{113 114} but some secondary responses observed in patients receiving a different aldesleukin-based regimen.¹¹³

Melanoma

Palliative treatment of metastatic melanoma in selected patients, alone and in combination with other agents^{1 5 68} including biologic response modifiers (e.g., interferon alfa),^{43 53 55 79 80 81 173} adoptive immunotherapy (e.g., LAK cells, TILs),^{30 31 47 51 65 66 70 71 74 75 76 78} and/or conventional chemotherapeutic agents (e.g., cisplatin, dacarbazine).^{68 82 171 172}

Although higher response rates with some combination regimens,^{15 52 65 68 85 100 101 172 176} improvement in survival not demonstrated and toxicity often is greater.^{30 52 65 66 81 101 171 172 174 175 176}

Despite initial response to aldesleukin, tumor relapse is common in patients with metastatic melanoma, particularly following partial response.¹¹³ Treatment of relapsed disease with the same aldesleukin-based therapy that produced the initial response rarely is effective,^{113 114} but some secondary responses observed in patients receiving a different aldesleukin-based regimen.¹¹³

Aldesleukin Dosage and Administration

General

• 
  

  To reduce or prevent adverse effects, premedication with antipyretics (including an NSAIA) and histamine H₂-receptor antagonists may be given.¹

  
  

Administration

Administer by IV infusion.^{1 3}

Also administered by sub-Q injection†.^{15 22 40 55}

IV Administration

For solution and drug compatibility information see Compatibility under Stability.

Allow solution to reach room temperature prior to IV infusion.¹

Use plastic (PVC) containers for more consistent delivery; drug may adhere to glass.^{1 52}

Do not use an inline filter.^{1 101}

Do not coadminister with other drugs in the same container.¹

Consult manufacturer and/or specialized references for instructions on preparation of solutions administered by continuous IV infusion† or sub-Q administration†.¹⁰¹

Reconstitution

Reconstitute vial containing 22 million units (1.3 mg) of the drug with 1.2 mL of sterile water for injection to provide a solution containing 18 million units (1.1 mg)/mL.¹

Direct sterile water for injection toward the side of the vial with gentle swirling to avoid excessive foaming of the solution; do not shake.¹

Dilution

Add appropriate reconstituted dose to 50 mL of 5% dextrose injection.^{1 101}

Solutions outside the range of 30–70 mcg/mL may result in increased variability in drug delivery; avoid use of such solutions for short-duration IV infusions.^{1 101} Manufacturer states that a larger or smaller volume of 5% dextrose injection may be used to maintain a concentration of 30–70 mcg/mL.^{1 101}

Rate of Administration

Administer over 15 minutes.^{1 101}

Dosage

Potency usually is expressed in international units (IU);^{1 3} because other units also have been reported (e.g., Cetus Units [CU], Roche Units [RU], Biologic Response Modifiers Program Units [BRMPU]) and are not equivalent (e.g., 1 RU = 3 IU, 1 CU = 6 IU), exercise care in interpreting published dosages and concentrations.^{3 101}

International units are stated as units rather than as IU to minimize medication errors that could result from misinterpretation of written orders employing IU.^b

When a vial containing 22 million units is reconstituted by adding 1.2 mL of sterile water for injection, each mL contains 18 million units of aldesleukin (equivalent to 1.1 mg of drug).¹

Optimum dosage and regimen for treatment of metastatic renal cell carcinoma^{15 31 34 39 40 49 52 54 55 99 101 103 111 116 143} or metastatic melanoma not established.^{15 52 66 101 170}

Administration of doses in excess of recommended dose associated with a more rapid onset of anticipated dose-limiting toxicities.¹

Tumor regression has continued for up to 12 months after 1 or more courses of therapy, but optimum duration of therapy not yet established.^{1 3}

Consult manufacturer and/or specialized references for instructions on alternative dosages administered by continuous IV infusion† or sub-q injection†.¹⁰¹

Adults

Renal Cell Cancer

Intermittent IV Infusion

600,000 units/kg over 15 minutes every 8 hours for 14 doses (5-day treatment cycle), followed by a 9-day rest period, and a second 5-day treatment cycle (600,000 units/kg over 15 minutes every 8 hours for 14 doses) for a maximum of 28 doses or until intolerable adverse effects develop.^{1 23 38 52 111} (See Dosage Modification for Toxicity and Contraindications for Retreatment under Dosage and Administration.)

Alternatively, some clinicians have used 720,000 units/kg over 15 minutes every 8 hours for a maximum of 15 doses per cycle, with a 10-day rest period between the 2 cycles.^{20 31}

Manufacturer recommends drug-free interval ≥7 weeks between treatment courses from date of previous hospital discharge;¹ however, some clinicians report using shorter rest periods (i.e., 2–4 weeks) between courses.⁵²

Evaluate patients approximately 4 weeks after completion of initial course of therapy and again immediately prior to scheduled start of next course.¹ Manufacturer states that further therapy with aldesleukin should be undertaken only if there is evidence of tumor regression following the last course and the patient has not developed serious toxicity that would contraindicate continuation.¹ Some clinicians believe stabilization of disease in absence of serious toxicity warrants continued therapy.^{52 101}

Continuous IV Infusion†

18 million units/m² daily for two 5-day cycles, with a drug-free interval of 5–8 days between cycles.^{15 32 35 36 37 38 97 115 119}

Sub-Q Injection†

18 million units daily for 5 days followed by a 2-day rest period.^{15 40} For additional cycles, 9 million units on days 1 and 2, followed by 18 million units daily for the next 3 days.^{15 40 52 101} Treatment cycles of 6 consecutive weeks separated by a 3-week drug-free period were used.⁴⁰

Melanoma

IV Infusion

600,000 units/kg over 15 minutes every 8 hours for 14 doses (5-day treatment cycle), followed by a 6- to 9-day rest period, then a second 5-day treatment cycle (600,000 units/kg over 15 minutes every 8 hours for 14 doses) for a maximum of 28 doses per course or until intolerable adverse effects develop.^{1 170}

Alternatively, some clinicians have used 720,000 units/kg over 15 minutes every 8 hours for a maximum of 15 doses per cycle, with a 10-day rest period between the 2 cycles.^{20 31}

Manufacturer recommends drug-free interval ≥7 weeks between treatment courses from date of previous hospital discharge;¹ however, some clinicians report using rest periods of 6–12 weeks between courses.¹⁷⁰

Evaluate patients approximately 4 weeks after completion of initial course of therapy and again immediately prior to scheduled start of next course.¹ Manufacturer states that further therapy with aldesleukin should be undertaken only if there is evidence of tumor regression following the last course and the patient has not developed serious toxicity that would contraindicate continuation.¹ Some clinicians believe stabilization of disease in absence of serious toxicity warrants continued aldesleukin therapy.^{52 101}

Dosage Modification for Toxicity and Contraindications for Retreatment

Contraindications for Retreatment^{1 52}

Retreatment is contraindicated in patients who have experienced the following toxicities:¹

Cardiovascular:

Sustained ventricular tachycardia (≥5 beats)

Cardiac rhythm disturbances, not controlled or unresponsive to management

Chest pain with ECG changes, consistent with angina or MI

GI:

Bowel ischemia/perforation

GI bleeding requiring surgery

Neurologic:

Coma or toxic psychosis lasting >48 hours

Repetitive or difficult-to-control seizures

Cardiac tamponade

Respiratory:

Intubation for >72 hours

Renal:

Renal failure requiring dialysis for >72 hours

Therapy Interruptions for Toxicity

Toxicities requiring dosage modification should involve withholding or interrupting a dose rather than reducing the individual dose to be given.¹

Therapy Interruptions for Toxicity Based on Manifestations

Toxicity	Hold dose for:	May give subsequent dose if:
Cardiovascular	Atrial fibrillation, supraventricular tachycardia, recurrent or persistent bradycardia or bradycardia requiring treatment1	Asymptomatic with complete recovery to normal sinus rhythm1
	SBP <90 mm Hg with increasing vasopressor requirements1	SBP ≥90 mm Hg and stable or improving vasopressor requirement 1
	ECG changes consistent with MI, ischemia, or myocarditis, with or without chest pain, or suspicion of cardiac ischemia1	Asymptomatic; MI and myocarditis ruled out; minimal clinical suspicion of angina; or no evidence of ventricular hypokinesia1
Dermatologic	Bullous dermatitis or marked worsening of preexisting skin condition; avoid topical corticosteroid therapy1	All signs of bullous dermatitis resolved1
GI	GI bleeding demonstrated by stool guaiac test repeatedly positive with a result >3+ or 4+1	Negative stool guaiac test results1
Hepatic	Signs of hepatic failure, including encephalopathy, increasing ascites, liver pain, or hypoglycemia1	When all signs of hepatic failure have resolved; initiate a new course of treatment (if warranted) ≥7 weeks after cessation of adverse events and hospital discharge1
Infectious complications	Sepsis syndrome occurs and patient is clinically unstable1	Sepsis syndrome resolved, patient is clinically stable and infection is being treated1
Neurologic	Changes in mental status (e.g., moderate confusion, agitation)1	Mental status changes completely resolved1
Renal	Scr ≥4.5 mg/dL or ≥4 mg/dL in presence of severe volume overload, acidosis, or hyperkalemia1	Scr <4 mg/dL and stable fluid and electrolyte status1
	Persistent oliguria with urine output <10 mL/hour for 16–24 hours with increasing Scr1	Urine output >10 mL/hour with a decrease in Scr of >1.5 mg/dL or normalization of Scr1
Respiratory	Oxygen saturation <90%1	Oxygen saturation ≥90%1

Prescribing Limits

Adults

Renal Cell Carcinoma or Melanoma

IV Infusion

Maximum 28 doses per course.¹

Special Populations

No special population dosage recommendations at this time.¹ Manufacturer states patients should have normal cardiac, pulmonary, hepatic, and CNS function at the start of therapy.¹ (See Patient Selection, CNS Effects, Hepatic Impairment, Renal Impairment, and Geriatric Use, all under Cautions.)

Cautions for Aldesleukin

Contraindications

• 
  

  Known history of hypersensitivity to IL-2 or any ingredient in the formulation.¹

  
  


• 
  

  Abnormal thallium stress test results.¹

  
  


• 
  

  Abnormal pulmonary function test results.¹

  
  


• 
  

  Organ allografts.¹

  
  


• 
  

  Further therapy contraindicated if certain toxicities developed during previous aldesleukin therapy (i.e., sustained ventricular tachycardia [≥5 beats], uncontrolled cardiac arrhythmias or arrhythmias unresponsive to management, chest pain with ECG changes consistent with angina or MI, cardiac tamponade, intubation for >72 hours, renal failure requiring dialysis for >72 hours, coma or toxic psychosis lasting >48 hours, repetitive or difficult to control seizures, bowel ischemia/perforation, or GI bleeding requiring surgery).¹ (See Dosage Modification for Toxicity and Contraindications for Retreatment under Dosage and Administration.)

  
  

Warnings/Precautions

Warnings

Patient Selection

Careful patient selection mandatory prior to initiation of drug, including assessment of cardiac, renal, hepatic, CNS, and pulmonary functions, blood chemistry, and blood cell counts.¹ (See Boxed Warning and also see Toxicity and Adequate Patient Monitoring under Cautions.)

However, even patients with normal cardiovascular, pulmonary, hepatic, and CNS function may experience adverse events.¹ Adverse effects are frequent, often serious, and sometimes fatal.^{1 6 15 20} Carefully weigh risks versus benefits of therapy.^{1 15 6 20} (See Contraindications under Cautions.)

Patients with favorable Eastern Cooperative Oncology Group performance status (ECOG PS 0) at treatment initiation have a higher response rate and lower toxicity; therefore, consider performance status during patient selection for treatment.^{1 111 112} Experience in patients with ECOG PS >1 extremely limited.¹

Autoimmune and Inflammatory Reactions

Possible development or exacerbation of autoimmune disease and inflammatory disorders when used alone or in combination with interferon alfa.¹ (See Specific Drugs under Interactions.)

Possible onset of symptomatic hyperglycemia and/or diabetes mellitus.¹

Possible hypothyroidism, sometimes preceded by hyperthyroidism, following treatment; may require thyroid hormone replacement therapy.¹ Hyperthyroidism also reported.¹

Increased risk of allograft rejection in transplant patients because of enhanced cellular immune function.¹

Exacerbation of Crohn’s disease, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome, and bullous pemphigoid reported.¹

CNS Effects

Thoroughly evaluate and treat all patients for CNS metastases; must have a negative CT scan prior to receiving therapy.¹

New neurologic manifestations (e.g., mental status changes, speech difficulties, cortical blindness, limb/gait ataxia, hallucinations, agitation, obtundation, coma) and anatomic lesions reported following aldesleukin therapy in patients without evidence of CNS metastases.^{1 6 8 9 15 20}

Mental status changes (e.g., irritability, confusion, depression, agitation, lethargy, somnolence) may be a direct result of CNS toxicity from aldesleukin or indicative of bacteremia, early bacterial sepsis, hypoperfusion, or occult CNS malignancy.¹ Aldesleukin-induced mental status changes generally reverse within several days after discontinuance of the drug,¹⁵ although may progress for several days before recovery begins.^{1 15 101} However, permanent neurologic defects reported.¹

Potential for seizures; use with extreme caution if known seizure disorders.¹

Sensitivity Reactions

Risk of anaphylaxis in patients receiving various treatment regimens that included aldesleukin.¹

Hypersensitivity reactions (e.g., erythema, pruritus, hypotension) reported within hours of administration of therapy in patients receiving combination regimens with sequential administration of high-dose aldesleukin and antineoplastic agents (specifically cisplatin, dacarbazine, tamoxifen, and interferon alfa);¹ medical intervention required in some patients.¹ (See Specific Drugs under Interactions.)

Potential for nonanaphylactic allergic reactions.¹⁴⁰

May predispose individuals to acute, atypical adverse reactions to iodinated radiographic contrast media.¹ (See Specific Drugs under Interactions.)

Major Toxicities

Capillary Leak Syndrome

Risk of CLS particularly at usual dosages recommended by the manufacturer; risk of severe, possibly fatal, hypotension and reduced organ perfusion.^{1 6 8 11 15 101} Begins immediately after treatment initiation; characterized by increased vascular permeability to proteins and fluids and reduced vascular tone.^{1 6 15} (See Boxed Warning.)

Monitor fluid and organ perfusion status carefully; frequently monitor BP, heart rate, and organ function, including assessment of mental status and urine output.¹ Assess hypovolemia by catheterization and central venous pressure monitoring.¹

If hypovolemia occurs, administration of IV fluids (e.g., colloid replacement fluids or crystalloids) recommended.¹ Use caution when administering large volumes of IV fluids to correct hypovolemia; unrestrained fluid administration may exacerbate complications associated with edema or effusions.¹

Use extreme caution when treating patients with fixed requirements for large volumes of fluid (e.g., those with hypercalcemia); flexibility in fluid and vasopressor management is essential for maintaining organ perfusion and BP.^{1 101}

Management of edema and ascites and/or effusions depends on careful balancing of fluid shifts to ensure that the consequences of hypovolemia (e.g., impaired organ perfusion) or fluid accumulation (e.g., pulmonary edema) do not exceed the patient’s tolerance.¹

Early administration of IV dopamine with or without IV phenylephrine hydrochloride before onset of hypotension can help maintain organ perfusion, particularly renal perfusion, and preserve urine output.¹ Exercise caution; prolonged use of vasopressors, alone or in combination, at relatively high doses may be associated with cardiac rhythm disturbances.¹

If adequate organ perfusion not maintained (demonstrated by altered mental status, reduced urine output, decrease in SBP to <90 mm Hg, or onset of cardiac arrhythmias), withhold subsequent aldesleukin doses until organ perfusion recovers and SBP ≥90 mm Hg.¹

Recovery from CLS begins within a few hours after discontinuance of aldesleukin therapy.¹ If excessive weight gain, edema or pulmonary congestion with shortness of breath occurs, diuretics may hasten recovery once BP normalized.¹

Flu-like Syndrome

Flu-like syndrome (e.g., fever [sometimes grade 4 or life-threatening], chills, rigors) possible.^{1 6 13 15} Other symptoms possible (e.g., pain,¹ abdominal pain,¹ malaise,¹ asthenia, ¹ arthralgia and/or myalgia, ^{15 140} chest pain,¹⁴⁰ back pain,¹⁴⁰ fatigue).¹⁴⁰

General Precautions

Toxicity and Adequate Patient Monitoring

Highly toxic drug; prior to initiation of therapy and daily during therapy, perform hematologic tests (e.g., CBC, differential, platelet counts), blood chemistries (e.g., serum electrolyte concentrations), renal and hepatic function tests, and chest radiographs.¹ (See Cardiovascular Effects, Pulmonary Effects, Renal Impairment, and Hepatic Impairment, all under Cautions.)

During therapy, monitor vital signs (i.e., temperature, pulse, BP, respiration rate) at least every 4 hours⁵² and patient’s weight and fluid intake and output daily.^{1 52} In hypotensive patients, monitor vital signs hourly.¹ If SBP decreases (especially to <90 mm Hg), perform constant cardiac rhythm monitoring.¹ (See Cardiovascular Effects under Cautions.)

Cardiovascular Effects

Prior to initiation of therapy, perform a stress thallium study to document normal cardiac ejection fraction and unimpaired myocardial wall motion.^{1 101} If results suggest minor wall motion abnormalities, test further to exclude CAD.¹ (See Boxed Warning.)

During therapy, assess cardiac function daily.¹ If signs or symptoms (e.g., chest pain, murmurs, gallops, irregular cardiac rhythm, palpitation), assess with an ECG and cardiac enzymes.¹ Evidence of myocardial injury, including findings compatible with MI or myocarditis, reported.¹ Ventricular hypokinesia caused by myocarditis may persist for several months.¹ If evidence of cardiac ischemia or CHF, withhold therapy and repeat thallium study.¹

Pulmonary Effects

Perform baseline pulmonary function tests with arterial blood gases in all patients.¹ Must have adequate pulmonary function (FEV₁ >2 L or >75% of predicted value based on height and age) prior to initiation of therapy.¹

Monitor pulmonary function regularly during therapy.¹ If dyspnea or clinical signs of respiratory impairment (i.e., tachypnea or rales), assess with arterial blood gases.¹ Repeat as often as clinically indicated.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether aldesleukin is distributed into milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹

Geriatric Use

Response, median number of doses per course, and median number of courses of therapy in patients ≥65 years of age does not appear to differ from that in younger adults; however, possible increased risk of toxicity in patients with renal impairment.¹ Possible increased incidence of severe urogenital toxicity and dyspnea compared with younger patients.¹

Hepatic Impairment

Aldesleukin therapy impairs hepatic function.¹ Normal hepatic function necessary at start of therapy.¹ (See Toxicity and Adequate Patient Monitoring under Cautions and also see Hepatotoxic Agents under Interactions.)

Renal Impairment

Contraindicated in patients who develop renal impairment requiring dialysis for >72 hours after a previous course of aldesleukin.¹

Aldesleukin therapy impairs renal function.¹ Preexisting renal impairment appears to be associated with an increased risk of more severe and prolonged renal dysfunction.^{10 15} (See Toxicity and Adequate Patient Monitoring under Cautions and also see Nephrotoxic Agents under Interactions.)

Manufacturer states that S_cr should be≤1.5 mg/dL prior to initiation of aldesleukin therapy.¹

Common Adverse Effects

Hypotension, diarrhea, renal dysfunction with oliguria, chills, vomiting, dyspnea, rash, bilirubinemia, thrombocytopenia, nausea, confusion, increased S_cr, anemia, fever, peripheral edema, malaise, lung disorders (e.g., pulmonary congestion, rales, rhonchi), pruritus, asthenia, tachycardia, increased AST, stomatitis, somnolence, anorexia.¹

Life-threatening or grade 4 adverse effects: Renal dysfunction with oliguria/anuria, hypotension, respiratory disorder (i.e., ARDS, respiratory failure, intubation), coma, bilirubinemia.¹

Interactions for Aldesleukin

Cardiotoxic Agents

Concurrent administration may increase risk of cardiotoxicity.¹

CNS-Active Agents

Concurrent administration may increase risk of CNS effects.¹

Hepatotoxic Agents

Concurrent administration may increase risk of hepatotoxicity. (See Hepatic Impairment under Cautions.)¹

Myelotoxic Agents

Concurrent administration may increase risk of myelotoxicity.¹

Nephrotoxic Agents

Concurrent administration may increase risk of nephrotoxicity. (See Renal Impairment under Cautions.)¹

Specific Drugs

Drug	Interaction	Comments
Aminoglycosides	Possible increase in nephrotoxicity1
Anthracyclines (e.g., doxorubicin)	Possible increase in cardiotoxicity1
Antihypertensive agents (e.g., β-blocking agents)	Possible increase in hypotensive effects1
Antineoplastic agents	Possible increased myelotoxicity1	Safety and efficacy not established1
Asparaginase	Possible increase in hepatotoxicity1
Cisplatin	Potential hypersensitivity reactions (erythema, pruritus, and hypotension)1	Medical intervention may be required1
CNS depressants (e.g., analgesics, antiemetics, opiate agonists, sedatives, tranquilizers)	Possible increased risk of CNS effects1
Corticosteroids (glucocorticoids)	Possible reduction of antitumor effectiveness1	Avoid concomitant use1
Dacarbazine	Potential hypersensitivity reactions (erythema, pruritus, and hypotension)1	Medical intervention may be required1
Indomethacin	Possible increase in nephrotoxicity1
Interferon alfa	Possible development or exacerbation of autoimmune disease and inflammatory disorders (e.g., thyroiditis,1 inflammatory arthritis,1 oculo-bulbar myasthenia gravis,1 crescentic IgA glomerulonephritis,1 155 Stevens-Johnson syndrome,1 or bullous pemphigoid)1 Possible increased incidence of myocardial injury (MI,1 myocarditis,1 ventricular hypokinesia,1 and severe rhabdomyolysis)1 Potential hypersensitivity reactions (erythema, pruritus, and hypotension)1	Medical intervention may be required1
Methotrexate	Possible increase in hepatotoxicity1
Roentgenographic agents	Potential acute, atypical adverse reactions (e.g., fever, chills, nausea, vomiting, diarrhea, pruritus, rash, hypotension, edema, oliguria)1 to iodinated radiographic contrast media 1	May occur when contrast media are administered up to several months after aldesleukin administration1
Tamoxifen	Potential hypersensitivity reactions (erythema, pruritus, and hypotension)1	Medical intervention may be required1

Aldesleukin Pharmacokinetics

Absorption

Bioavailability

Approximately 30% of a dose detectable in plasma upon completion of IV infusion.¹

Distribution

Extent

Rapidly distributed into extravascular space; animal studies indicate rapid (<1 minute) uptake into lung, liver, kidney, and spleen.¹

Not known whether aldesleukin is distributed into milk.¹

Elimination

Metabolism

Metabolized principally in the kidney.¹

Elimination Route

Excreted in urine; little or no active drug detected.¹

Half-life

85 minutes.¹

Stability

Storage

Parenteral

Powder for Injection

Store in carton at 2–8°C until used; protect from light.¹

Preferably, store reconstituted or diluted solution at 2–8°C.¹ Alternatively, store at room temperature for ≤48 hours.¹ Do not freeze.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible1
Dextrose 5% in water
Sterile water for injection
Incompatible1
Bacteriostatic water for injection
Sodium chloride 0.9%

Drug Compatibility

Y-Site Compatibilitya

Compatible
Amikacin sulfate
Amphotericin B
Calcium gluconate
Co-trimoxazole
Diphenhydramine HCl
Fat emulsion, IV
Fluconazole
Foscarnet sodium
Gentamicin sulfate
Magnesium sulfate
Metoclopramide HCl
Morphine sulfate
Ondansetron HCl
Variable
Ranitidine HCI
Thiethylperazine malate
Tobramycin
Vancomycin
Incompatible
Fluorouracil
Ganciclovir sodium
Lorazepam
Pentamidine isethionate
Prochlorperazine edisylate
Promethazine HCl
Variable
Dopamine HCl
Heparin sodium
Potassium chloride

ActionsActions

• 
  

  Biologic response modifier; possesses biologic activities of IL-2.¹

  
  


• 
  

  Precise mechanism of action unknown; whether effects on immune system contribute to antineoplastic activity not established.¹

  
  


• 
  

  Exerts a wide range of regulatory actions on the immune system in vitro, including enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human IL-2 dependent cell lines, enhancement of lymphocyte cytotoxicity, induction of LAK cell and natural killer (NK) cell activity, and induction of interferon-gamma production.¹

  
  


• 
  

  Produces immune effects in a dose-dependent manner.¹ Activates cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia; stimulates production of cytokines (e.g., tumor necrosis factor, IL-1, interferon gamma).¹

  
  

Advice to Patients

• 
  

  Risk of serious, life-threatening, or fatal adverse effects in patients with normal cardiovascular, pulmonary, hepatic, or CNS function.¹

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular or pulmonary disease).¹

  
  


• 
  

  Importance of informing patients of other important precautio

Alsuma

sumatriptan

Dosage Form: auto-injector injection, solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Alsuma

Acute Treatment of Migraine Attacks and Cluster Headache

Alsuma (sumatriptan injection) 6 mg/0.5 mL is indicated for the acute treatment of migraine attacks, with or without aura, and the acute treatment of cluster headache episodes.

Important Limitations

Alsuma should only be used where a clear diagnosis of migraine or cluster headache has been established. Care should be taken to exclude other potentially serious neurologic conditions before treating headache in patients not previously diagnosed with migraine or cluster headache or who experience a headache that is atypical for them.

For a given attack, if a patient does not respond to the first dose of Alsuma, the diagnosis of migraine or cluster headache should be reconsidered before administration of a second dose.

Alsuma is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. [see Contraindications (4.7)]

Alsuma Dosage and Administration

Alsuma is only for subcutaneous use.

The maximum single recommended adult dose of Alsuma is 6 mg injected subcutaneously. The maximum recommended dose that may be given in 24 hours is two doses of Alsuma separated by at least 1 hour. Controlled clinical trials have failed to show that clear benefit is associated with the administration of a second 6 mg dose in patients who have failed to respond to a first dose.

Since the injection is intended to be given subcutaneously, intramuscular or intravascular delivery must be avoided. Patients should be directed to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle. Alsuma is for single use only. Discard unused portions. [see Patient Counseling Information (17.5)]

Dosage Forms and Strengths

Alsuma contains 6 mg of sumatriptan (as 8.4mg sumatriptan succinate), which is delivered as a subcutaneous injection in a single dose. Alsuma is supplied as a single-use auto-injector pre-filled with sumatriptan succinate drug solution and fully-assembled for use.

Contraindications

Intravenous Administration

Alsuma is not designed to administer sumatriptan intravenously. Do not administer intravenously since sumatriptan may cause coronary vasospasm.

Ischemic or Vasospastic Coronary Artery Disease

Do not use Alsuma in patients with ischemic heart disease (e.g. angina pectoris, history of myocardial infarction, or documented silent ischemia), or to patients who have symptoms or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal’s variant angina or other significant underlying cardiovascular disease. [see Warnings and Precautions (5.1)]

Cerebrovascular Syndromes

Do not use Alsuma in patients with cerebrovascular syndromes including (but not limited to) strokes of any type as well as transient ischemic attacks. [see Warnings and Precautions (5.3)]

Peripheral Vascular Disease

Do not use Alsuma in patients with peripheral vascular disease including (but not limited to) ischemic bowel disease. [see Warnings and Precautions (5.4)]

Uncontrolled Hypertension

Because Alsuma may increase blood pressure, do not use in patients with uncontrolled hypertension. [see Warnings and Precautions (5.6)]

Do Not Use Within 24 hours of Treatment with Ergotamine-Containing or Ergot-Type Medications or Other 5-HT1 Agonists (e.g. Triptans)

Do not use Alsuma and any ergotamine-containing or ergot-type medication (such as dihydroergotamine or methysergide) within 24 hours of each other; do not use Alsuma and another 5-HT1 agonist (e.g. triptan) within 24 hours of each other. [see Drug Interactions (7.3)]

Hemiplegic or Basilar Migraine

Do not use Alsuma in patients with hemiplegic or basilar migraine.

Hypersensitivity

Alsuma is contraindicated in patients with known hypersensitivity to sumatriptan or any of its components.

Warnings and Precautions

Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events

Cardiac Events and Fatalities with 5-HT1 Agonists

Serious adverse cardiac events, including acute myocardial infarction, life threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of sumatriptan. Considering the extent of use of sumatriptan in patients with migraine, the incidence of these events is extremely low.

Sumatriptan can cause coronary vasospasm. Some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD with close proximity of the events to sumatriptan use. Because Alsuma may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following Alsuma administration should be evaluated for the presence of CAD or a predisposition to Prinzmetal variant angina before receiving additional doses of sumatriptan and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur.

Premarketing Experience with Sumatriptan

Among the more than 1,900 patients with migraine who participated in reported premarketing controlled clinical trials of subcutaneous sumatriptan, there were 8 patients who sustained clinical events during or shortly after receiving sumatriptan that may have reflected coronary artery vasospasm. Six of these 8 patients had ECG changes consistent with transient ischemia, without accompanying clinical symptoms or signs. Of these 8 patients, 4 had either findings suggestive of CAD or risk factors predictive of CAD prior to study enrollment.

Of 6,348 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of oral sumatriptan, 2 experienced clinical adverse events shortly after receiving oral sumatriptan that may have reflected coronary vasospasm. Neither of these adverse events was associated with a serious clinical outcome.

Among approximately 4,000 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of sumatriptan nasal spray, 1 patient experienced an asymptomatic subendocardial infarction possibly subsequent to a coronary vasospastic event.

Postmarketing Experience with Sumatriptan

Serious cardiovascular events, some resulting in death, have been reported in association with the use of subcutaneous sumatriptan injection. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by sumatriptan or to reliably assess causation in individual cases. On clinical grounds, the longer the latency between the administration of sumatriptan and the onset of the clinical event, the less likely the association is to be causative. Interest has focused on events beginning within 1 hour of the administration of sumatriptan.

Cardiac events that have been observed to have onset within 1 hour of sumatriptan administration include coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death.

Some of these events occurred in patients who had no findings of CAD and appear to represent consequences of coronary artery vasospasm. However, among reports of serious cardiac events within 1 hour of sumatriptan administration, the majority had risk factors predictive of CAD, and the presence of significant underlying CAD was established in most cases. [see Contraindications (4.2)]

Patients with Documented Coronary Artery Disease

Because of the potential of this class of compound (5-HT1 agonists) to cause coronary vasospasm, Alsuma should not be given to patients with documented ischemic or vasospastic coronary artery disease. [see Contraindications (4.2)]

Patients with Risk Factors for CAD

It is strongly recommended that Alsuma not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoking, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of or consistent with coronary artery vasospasm or myocardial ischemia, Alsuma should not be administered. [see Contraindications (4.2)]

For patients with risk factors predictive of CAD who have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of Alsuma take place in the setting of a physician’s office or similar medically staffed and equipped facility. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining, on the first occasion of use, an electrocardiogram (ECG) during the interval immediately following use of Alsuma in these patients with risk factors.

It is recommended that patients who are intermittent long-term users of Alsuma and who have or acquire risk factors predictive of CAD, as described above, undergo cardiovascular evaluation periodically as they continue to use sumatriptan. In considering this recommendation for periodic cardiovascular evaluation, it is noted that patients with cluster headache are predominantly male and over 40 years of age, which are risk factors for CAD.

Sensations of Pain, Tightness, Pressure in the Chest and/or Throat, Neck and Jaw

Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw are relatively common after treatment with sumatriptan. Only rarely have these symptoms been associated with ischemic ECG changes.

However, because sumatriptan may cause coronary vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal’s variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms occur. Patients shown to have CAD and those with Prinzmetal’s variant angina should not receive 5-HT1 agonists. [see Contraindications (4.2) and Warnings and Precautions (5.1)]

Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud syndrome, following sumatriptan should be evaluated for atherosclerosis or predisposition to vasospasm. [see Contraindications (4.4) and Warnings and Precautions (5.4)]

Drug-Associated Cerebrovascular Events and Fatalities

Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with subcutaneous sumatriptan, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, sumatriptan having been administered in the incorrect belief the symptoms experienced were a consequence of migraine when they were not. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should also be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). [see Contraindications (4.3)]

Other Vasospasm-Related Events, including Peripheral Vascular Ischemia and Colonic Ischemia

5-HT1 agonists, including Alsuma, may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported.

Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of sumatriptan. Visual disorders may also be part of a migraine attack.

Patients who experience other symptoms or signs suggestive of decreased arterial flow following the use of any 5-HT1 agonist, such as ischemic bowel syndrome or Raynaud’s syndrome, are candidates for further evaluation. [see Contraindications (4.4)]

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including Alsuma, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). [see Drug Interactions (7.4)]

Increase in Blood Pressure

Alsuma is contraindicated in patients with uncontrolled hypertension. Sumatriptan should be administered with caution to patients with controlled hypertension, as transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients. Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients with and without a history of hypertension. [see Contraindications (4.5)]

Concomitant MAO-A Inhibitors

The coadministration of Alsuma and an MAO-A inhibitor is not generally recommended. In patients taking MAO-A inhibitors, sumatriptan plasma levels are nearly doubled. If such therapy is clinically warranted, however, suitable dose adjustment (e.g. using a different sumatriptan product, as Alsuma only exists as a 6mg sumatriptan auto-injector) and appropriate observation of the patient are advised. [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]

Hypersensitivity

Hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred on rare occasions in patients receiving sumatriptan. Such reactions can be life threatening or fatal. [see Contraindications (4.8)]

Seizures

There have been rare reports of seizure following administration of sumatriptan. Sumatriptan should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

Pregnancy

Alsuma should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. [see Use in Specific Populations (8.1)]

Corneal Opacities

Sumatriptan causes corneal opacities and defects in the corneal epithelium in dogs; this raises the possibility that these changes may occur in humans. While patients were not systematically evaluated for these changes in clinical trials, and no specific recommendations for monitoring are being offered, prescribers should be aware of the possibility of these changes. [see Nonclinical Toxicology (13.2)]

Adverse Reactions

This section provides a summary of adverse reactions reported in subjects in clinical studies conducted with Alsuma and sumatriptan injection. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug, and may not reflect the rates observed in practice.

Serious cardiac reactions, including myocardial infarction, have occurred following the use of sumatriptan. These reactions are extremely rare and most have been reported in patients with risk factors predictive of CAD. Reactions reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation. [see Contraindications (4.2) and Warnings and Precautions (5.1)]

Significant hypertensive episodes, including hypertensive crises, have been reported on rare occasions in patients with or without a history of hypertension. [see Warnings and Precautions (5.6)]

The following other adverse reactions are discussed in more detail in other sections of labeling:

Sensations of Chest Pain and Tightness [see Warnings and Precautions (5.2)]

Cerebrovascular Events and Fatalities [see Warnings and Precautions (5.3)]

Other Vasospasm related Events including Peripheral Vascular Ischemia and Colonic Ischemia [see Warnings and Precautions (5.4)]

Serotonin Syndrome [see Warnings and Precautions (5.5)]

Among patients in clinical trials of subcutaneous sumatriptan succinate injection (n=6,218), up to 3.5% of patients withdrew for reasons related to adverse reactions.

Controlled Clinical Trials in Patients with Migraine Headache

Table 1 lists adverse reactions that occurred in 2 large placebo-controlled clinical trials in migraine patients following either a single 6 mg sumatriptan injection or placebo. Only adverse reactions that occurred at a frequency of 2% or more in groups treated with sumatriptan injection 6 mg and occurred at a frequency greater than in the placebo group are included in Table 1.

Table 1. Treatment-Emergent Adverse Reactions Incidence in 2 Large, Placebo-Controlled Clinical Trials in Patients with Migraine: Events Reported by at Least 2% of Patients Treated with Sumatriptan Injection 6 mg*

	Percent of Patients Reporting
Adverse Reactions	Sumatriptan 6 mg SC (n = 547)	Placebo (n = 370)
Atypical sensations Tingling Warm/hot sensation Burning sensation Feeling of heaviness Pressure sensation Feeling of tightness Numbness Feeling strange Tight feeling in head	42 14 11 7 7 7 5 5 2 2	9 3 4 <1 1 2 <1 2 <1 <1
Cardiovascular Flushing	- 7	- 2
Chest Discomfort Tightness in chest Discomfort: nasal cavity/sinuses	5 3 2	1 <1 <1
Injection site reaction	59	24
Miscellaneous Jaw discomfort Musculoskeletal Weakness Neck pain/stiffness Myalgia	- 2 - 5 5 2	- 0 - <1 <1 <1
Neurological Dizziness/vertigo Drowsiness/sedation Headache	- 12 3 2	- 4 2 <1
* The sum of the percentages cited is greater than 100% because patients could have experienced more than 1 type of adverse event. Only events that occurred at a frequency of 2% or more in groups treated with sumatriptan injection and that occurred at a frequency greater than that in the placebo group are included.

The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse events.

Controlled Clinical Trials in Patients with Cluster Headache

In the controlled clinical trials assessing sumatriptan injection as a treatment for cluster headache, no new significant adverse reactions associated with the use of sumatriptan were detected that had not already been identified in association with the drug’s use in migraine.

Overall, the frequency of adverse events reported in studies of cluster headache was generally lower. Exceptions include reports of paresthesia (5% sumatriptan, 0% placebo), nausea and vomiting (4% sumatriptan, 0% placebo), and bronchospasm (1% sumatriptan, 0% placebo).

Other Adverse Reactions Observed in Association with the Administration of Sumatriptan Injection

The frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include events observed in open and uncontrolled studies, the role of sumatriptan injection in their causation cannot be reliably determined. Furthermore, variability associated with adverse reactions reporting, the terminology used to describe adverse reactions limits the value of the quantitative frequency estimates provided.

Adverse reactions frequencies are calculated as the number of patients reporting an event divided by the total number of patients (N = 6,218) exposed to subcutaneous sumatriptan. All reported adverse reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Adverse reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring in at least 1/100 patients, infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients, and rare adverse reactions are those occurring in fewer than 1/1,000 patients.

Cardiovascular: Infrequent were hypertension, hypotension, bradycardia, tachycardia, palpitations, pulsating sensations, various transient ECG changes (nonspecific ST or T-wave changes, prolongation of PR or QTc intervals, sinus arrhythmia, nonsustained ventricular premature beats, isolated junctional ectopic beats, atrial ectopic beats, delayed activation of the right ventricle), and syncope. Rare were pallor, arrhythmia, abnormal pulse, vasodilation, and Raynaud syndrome.

Endocrine and Metabolic: Infrequent was thirst. Rare were polydipsia and dehydration.

Eye: Frequent were vision alterations. Infrequent was irritation of the eye.

Gastrointestinal: Frequent were abdominal discomfort and dysphagia. Infrequent were gastroesophageal reflux and diarrhea. Rare were peptic ulcer, retching, flatulence/eructation, and gallstones.

Musculoskeletal: Frequent were muscle cramps. Infrequent were various joint disturbances (pain, stiffness, swelling, ache). Rare were muscle stiffness, need to flex calf muscles, backache, muscle tiredness, and swelling of the extremities.

Neurological: Frequent was anxiety. Infrequent were mental confusion, euphoria, agitation, relaxation, chills, sensation of lightness, tremor, shivering, disturbances of taste, prickling sensations, paresthesia, stinging sensations, facial pain, photophobia, and lacrimation. Rare were transient hemiplegia, hysteria, globus hystericus, intoxication, depression, myoclonia, monoplegia/diplegia, sleep disturbance, difficulties in concentration, disturbances of smell, hyperesthesia, dysesthesia, simultaneous hot and cold sensations, tickling sensations, dysarthria, yawning, reduced appetite, hunger, and dystonia.

Respiratory: Infrequent was dyspnea. Rare were influenza, diseases of the lower respiratory tract, and hiccoughs.

Skin: Infrequent were erythema, pruritus, and skin rashes and eruptions. Rare was skin tenderness.

Urogenital: Rare were dysuria, frequency, dysmenorrhea, and renal calculus.

Miscellaneous: Infrequent were miscellaneous laboratory abnormalities, including minor disturbances in liver function tests, “serotonin agonist effect,” and hypersensitivity to various agents. Rare was fever.

Other Adverse Reactions Observed in the Clinical Development of Sumatriptan

The following adverse reactions occurred in clinical trials with sumatriptan tablets and sumatriptan nasal spray. Because the reports include events observed in open and uncontrolled studies, the role of sumatriptan in their causation cannot be reliably determined. All reported events are included except those already listed, those too general to be informative, and those not reasonably associated with the use of the drug.

Breasts: Breast swelling, cysts, disorder of breasts, lumps, masses of breasts, nipple discharge, primary malignant breast neoplasm, and tenderness.

Cardiovascular: Abdominal aortic aneurysm, angina, atherosclerosis, cerebral ischemia, cerebrovascular lesion, heart block, peripheral cyanosis, phlebitis, thrombosis, and transient myocardial ischemia.

Ear, Nose, and Throat: Allergic rhinitis; disorder of nasal cavity/sinuses; ear, nose, and throat hemorrhage; ear infection; external otitis; feeling of fullness in the ear(s); hearing disturbances; hearing loss; Meniere disease; nasal inflammation; otalgia; sensitivity to noise; sinusitis; tinnitus; and upper respiratory inflammation.

Endocrine and Metabolic: Elevated thyrotropin stimulating hormone (TSH) levels; endocrine cysts, lumps, and masses; fluid disturbances; galactorrhea; hyperglycemia; hypoglycemia; hypothyroidism; weight gain; and weight loss.

Eye: Accommodation disorders, blindness and low vision, conjunctivitis, disorders of sclera, external ocular muscle disorders, eye edema and swelling, eye hemorrhage, eye itching, eye pain, keratitis, mydriasis, and visual disturbances.

Gastrointestinal: Abdominal distention, colitis, constipation, dental pain, dyspeptic symptoms, feelings of gastrointestinal pressure, gastric symptoms, gastritis, gastroenteritis, gastrointestinal bleeding, gastrointestinal pain, hematemesis, hypersalivation, hyposalivation, intestinal obstruction, melena, nausea and/or vomiting, oral itching and irritation, pancreatitis, salivary gland swelling, and swallowing disorders.

Hematological Disorders: Anemia.

Mouth and Teeth: Disorder of mouth and tongue (e.g., burning of tongue, numbness of tongue, dry mouth).

Musculoskeletal: Acquired musculoskeletal deformity, arthralgia and articular rheumatitis, arthritis, intervertebral disc disorder, muscle atrophy, muscle tightness and rigidity, musculoskeletal inflammation, and tetany.

Neurological: Apathy, aggressiveness, bad/unusual taste, bradylogia, cluster headache, convulsions, depressive disorders, detachment, disturbance of emotions, drug abuse, facial paralysis, hallucinations, heat sensitivity, incoordination, increased alertness, memory disturbance, migraine, motor dysfunction, neoplasm of pituitary, neuralgia, neurotic disorders, paralysis, personality change, phobia, phonophobia, psychomotor disorders, radiculopathy, raised intracranial pressure, rigidity, stress, syncope, suicide, and twitching.

Respiratory: Asthma, breathing disorders, bronchitis, cough, and lower respiratory tract infection.

Skin: Dry/scaly skin, eczema, herpes, seborrheic dermatitis, skin nodules, tightness of skin, and wrinkling of skin.

Urogenital: Abnormal menstrual cycle, abortion, bladder inflammation, endometriosis, hematuria, increased urination, inflammation of fallopian tubes, intermenstrual bleeding, menstruation symptoms, micturition disorders, urethritis, and urinary infections.

Miscellaneous: Contusions, difficulty in walking, edema, hematoma, hypersensitivity, fever, fluid retention, lymphadenopathy, overdose, speech disturbance, swelling of extremities, swelling of face, and voice disturbances.

Pain and Other Pressure Sensations: Chest pain and/or heaviness, neck/throat/jaw pain/tightness/pressure, and pain (location specified).

Postmarketing Experience (Reports for Subcutaneous or Oral Sumatriptan)

The following adverse reactions have been identified during postapproval use of Sumatriptan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. However, systemic reactions following sumatriptan use are likely to be similar regardless of route of administration.

Blood: Hemolytic anemia, pancytopenia, thrombocytopenia.

Cardiovascular: Atrial fibrillation, cardiomyopathy, colonic ischemia [see Warnings and Precautions (5.5)], Prinzmetal variant angina, pulmonary embolism, shock, thrombophlebitis.

Ear, Nose, and Throat: Deafness.

Eye: Ischemic optic neuropathy, retinal artery occlusion, retinal vein thrombosis, loss of vision.

Gastrointestinal: Ischemic colitis with rectal bleeding [see Warnings and Precautions (5.5)], xerostomia.

Hepatic: Elevated liver function tests.

Neurological: Central nervous system vasculitis, cerebrovascular accident, dysphasia, serotonin syndrome, subarachnoid hemorrhage.

Non-Site Specific: Angioneurotic edema, cyanosis, death [see Warnings and Precautions (5.3)], temporal arteritis.

Psychiatry: Panic disorder.

Respiratory: Bronchospasm in patients with and without a history of asthma.

Skin: Exacerbation of sunburn, hypersensitivity reactions (allergic vasculitis, erythema, pruritus, rash, shortness of breath, urticaria; in addition, severe anaphylaxis/anaphylactoid reactions have been reported [see Warnings and Precautions (5.8)]), photosensitivity. Following subcutaneous administration of sumatriptan, pain, redness, stinging, induration, swelling, contusion, subcutaneous bleeding, and, on rare occasions, lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) has been reported.

Urogenital: Acute renal failure.

Adverse Reactions Observed In Association With The Administration of Alsuma

The safety of Alsuma was evaluated in an open-label clinical trial evaluating the usability of Alsuma during a migraine attack. Adverse reactions that occurred at a frequency of 5% or higher were injection site bruising (16%), injection site pain (6%), and injection site hemorrhage (6%).

Drug Interactions

Monoamine Oxidase Inhibitors

MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan in patients receiving MAO-A inhibitors is not ordinarily recommended. If the clinical situation warrants the combined use of sumatriptan and an MAOI, the dose of sumatriptan employed should be reduced. [see Warnings and Precautions (5.7)and Clinical Pharmacology (12.3)]

5-HT1B/1D agonists (e.g. triptans)

Concomitant use of other 5-HT1B/1D agonists within 24 hours of sumatriptan treatment is not recommended. [see Contraindications (4.6)]

Ergot-Containing Drugs

Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Since these effects may be additive, use of ergotamine containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. [see Contraindications (4.6)]

Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome

Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with sumatriptan injection is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. [see Warnings and Precautions (5.5)]

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C. Sumatriptan produced evidence of developmental toxicity (embryolethality and increased incidences of fetal abnormalities) in rabbits. Embryolethality was observed at a dose less than the maximum recommended human dose (MRHD) of 12 mg/day on a body surface area (mg/m2) basis. There are no adequate and well-controlled studies of Alsuma in pregnant women. Alsuma should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When sumatriptan was administered intravenously to pregnant rabbits daily throughout the period of organogenesis, embryolethality was observed at doses at or close to those producing maternal toxicity. These doses were less than the MRHD of 12 mg/day on a mg/m2 basis. Oral administration of sumatriptan to rabbits during organogenesis was associated with increased incidences of fetal vascular and skeletal abnormalities. The highest no-effect dose for these effects was 15 mg/kg/day. The intravenous administration of sumatriptan to pregnant rats throughout organogenesis at doses that are approximately 10 times the MRHD on a mg/m2 basis, did not produce evidence of embryolethality. The subcutaneous administration of sumatriptan to pregnant rats prior to and throughout pregnancy did not produce evidence of embryolethality or teratogenicity.

Nursing Mothers

Sumatriptan is excreted in human breast milk following subcutaneous administration. Therefore, caution should be exercised when considering the administration of Alsuma to a nursing woman.

Pediatric Use

Safety and effectiveness of sumatriptan injection in pediatric patients under 18 years of age have not been established; therefore, sumatriptan injection is not recommended for use in patients under 18 years of age.

Two controlled clinical trials evaluating sumatriptan nasal spray (5 to 20 mg) in pediatric patients aged 12 to 17 years enrolled a total of 1,248 adolescent migraineurs who treated a single attack. The studies did not establish the efficacy of sumatriptan nasal spray compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults.

Five controlled clinical trials (2 single-attack studies, 3 multiple-attack studies) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These studies did not establish the efficacy of oral sumatriptan compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse events in these patients appeared to be both dose- and age-dependent, with younger patients reporting events more commonly than older adolescents.

Postmarketing experience documents that serious adverse events have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include events similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration.

Geriatric Use

The use of Alsuma in elderly patients is not recommended because they are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly. [see Warnings and Precautions (5.1, 5.6 )]

Overdosage

Patients (N = 269) have received single injections of 8 to 12 mg sumatriptan without significant adverse effects. Volunteers (N = 47) have received single subcutaneous doses of up to 16 mg without serious adverse events.

No gross overdoses in clinical practice have been reported. The half-life of elimination of sumatriptan is about 2 hours [see Clinical Pharmacology (12.3)], and therefore monitoring of patients after overdose with subcutaneous sumatriptan should continue while symptoms or signs persist, and for at least 10 hours. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

Alsuma Description

Sumatriptan is a selective 5-hydroxy-tryptamine receptor subtype 1 (5-HT1) agonist. Sumatriptan delivered as the succinate salt is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure:

The empirical formula is C14H21N3O2S • C4H6O4, representing a molecular weight of 413.5.

Alsuma is a clear, colorless to pale yellow, sterile, non-pyrogenic solution for subcutaneous injection. Each 0.5 mL of Alsuma 12 mg/mL solution contains 6 mg of sumatriptan (base) as the succinate salt and 3.5 mg of sodium chloride, USP in Water for Injection, USP. The pH range of the solution is approximately 4.2 to 5.3.

Alsuma - Clinical Pharmacology

Mechanism of Action

Sumatriptan is the active component of Alsuma. Sumatriptan is a selective agonist for the 5-HT1B and 5-HT1D receptors. Sumatriptan presumably exerts its antimigrainous effect through binding to vascular 5-HT1-type receptors, which have been shown to be present on cranial arteries in both dog and primate, on the human basilar artery, and in the vasculature of the isolated dura mater of humans. In these tissues, sumatriptan activates this receptor to cause vasoconstriction, an action in humans correlating with the relief of migraine and cluster headache.

Pharmacodynamics

Blood Pressure: Alsuma is contraindicated in patients with uncontrolled hypertension. [see Contraindications (4.5)] It should be administered with caution to patients with controlled hypertension. [see Warnings and Precautions (5.6)]

Peripheral (Small) Arteries: In healthy volunteers (N = 18), a study evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance.

Heart Rate: Transient increases in blood pressure observed in some patients in clinical studies carried out during sumatriptan’s development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate.

Respiratory Rate: Experience gained during the clinical development of sumatriptan as a treatment for migraine failed to detect an effect of the drug on respiratory rate.

Pharmacokinetics

Absorption and Elimination

Pharmacokinetic parameters following a 6 mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age, 33 years; mean weight, 77 kg) were systemic clearance: 1,194 ± 149 mL/min (mean ± S.D.), distribution half-life: 15 ± 2 minutes, terminal half-life: 115 ± 19 minutes, and volume of distribution central compartment: 50 ± 8 liters. Of this dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the indole acetic acid metabolite.

After a single 6 mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age, 24 ± 6 years; weight, 70 kg), the maximum serum concentration (Cmax) was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (Tmax) was 12 minutes after injection (range, 5 to 20 minutes). In this study, the same dose injected subcutaneously in the thigh gave a Cmax of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by auto-injector techniques. The Tmax or amount absorbed was not significantly altered by either the site or technique of injection.

The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97% ± 16% of that obtained following intravenous injection. Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL, is low, approximately 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated.

Drug Interactions

Monoamine Oxidase Inhibitors

In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme. In a study of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of sumatriptan, resulting in a two-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life.

Migraine Prophylactic Medications

There is no evidence that concomitant use of migraine prophylactic medications has any effect on the efficacy of sumatriptan. In 2 clinical trials in the United States, a retrospective analysis of 282 patients who had been using prophylactic drugs (verapamil, n = 63; amitriptyline, n = 57; propranolol, n = 94; for 45 other drugs, n = 123) were compared to those who had not used prophylaxis (n = 452). There were no differences in relief rates at 60 minutes postdose for sumatriptan injection, whether or not prophylactic medications were used.

Special Populations

Renal Impairment: The effect of renal impairment on the pharmacokinetics of sumatriptan has not been examined, but little clinical effect would be expected as sumatriptan is largely metabolized to an inactive substance.

Hepatic Impairment: The effect of hepatic disease on the pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were no statistically significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in hepatically impaired patients compared to healthy controls.

Age: The pharmacokinetics of sumatriptan in the elderly (mean age, 72 years, 2 males and 4 females) and in patients with migraine (mean age, 38 years, 25 males and 155 females) were similar to those in healthy male subjects (mean age, 30 years).

Race: The systemic clearance and Cmax of sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects.

Nonclinical Toxicology