Sumatriptan

Class: Selective Serotonin Agonists
VA Class: CN105
Chemical Name: C14H21N3O2S
Molecular Formula: C₁₄H₂₁N₃O₂S•C₄H₆O₄
CAS Number: 103628-46-2
Brands: Imitrex

REMS:

FDA approved a REMS for sumatriptan to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of sumatriptan and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Selective serotonin (5-hydroxytryptamine; 5-HT) type 1-like receptor agonist (“triptan”).^{1 2 3 4 5 6 7 8 223 224 268}

Uses for Sumatriptan

Vascular Headaches

Acute treatment of migraine attacks with or without aura.^{1 2 3 6 7 8 9 10 13 48 80 145 148 184 195 214 217 225 249}

Sub-Q for acute treatment of cluster headache episodes.^{1 2 49 75 183 184 185 210 214} Safety and efficacy of oral or intranasal sumatriptan for this use not established.^{148 249}

Not recommended for management of hemiplegic or basilar migraine or for prophylaxisof migraine or cluster headache.^{1 7 114 158}

Sumatriptan Dosage and Administration

Administration

Administer orally, intranasally, or by sub-Q injection. Do not administer IM or IV; IV administration may induce coronary vasospasm.^{1 148 249}

To achieve maximum relief, initiate therapy as soon as possible after onset of migraine attack.^{50 92 108 124 148 180 237}

Oral Administration

Administer orally with fluids; swallow tablet whole.¹⁴⁸

Intranasal Administration

Administer intranasally as a single spray into 1 nostril.²⁴⁹

Nasal solution unit contains only 1 spray; do not test before use.²⁴⁹

To administer, remove unit from package just before use.²⁴⁹ While sitting down, gently blow nose to clear nasal passages.²⁴⁹ Keep head in upright position and gently close 1 nostril with index finger; exhale gently through mouth.²⁴⁹ With other hand, hold unit with thumb supporting at bottom and index and middle fingers on either side of nozzle.²⁴⁹ Insert nozzle into open nostril about ½ inch.²⁴⁹ While gently inhaling through nose (with closed mouth), release spray by firmly pressing plunger.²⁴⁹ Remove nozzle from nostril while keeping head level for 10–20 seconds and gently inhaling through nose and exhaling through mouth; do not inhale deeply.²⁴⁹ Consult administration instructions provided by manufacturer before use.²⁴⁹

Sub-Q Administration

Administer only by sub-Q injection, preferably into lateral aspect of thigh or deltoid.^{1 12}

Do not administer IM or IV; IV administration may induce coronary vasospasm.¹

Autoinjection device available for use with prefilled syringes (each containing a 4- or 6-mg dose) to facilitate self-administration.^{1 273} Needles with this device penetrate approximately 5–6 mm (¼ inch); use injection sites with an adequate skin and subcutaneous thickness to accommodate needle length.^{1 273}

Dosage

Available as sumatriptan (nasal solution) and sumatriptan succinate (tablets and injection); dosage expressed in terms of sumatriptan.^{1 148 249}

Following failure to respond to first dose, reconsider diagnosis of migraine prior to administration of a second dose.^{1 148 249}

Adults

Vascular Headaches

Migraine

Oral

25, 50, or 100 mg as a single dose.^{148 274} Individualize dosage selection, weighing the possible benefit (greater effectiveness) and risks (increased adverse effects) of the 50- or 100-mg dose; 100-mg dose may not provide substantially greater effect than 50-mg dose.^{148 274}

If headache recurs or partial response occurs after initial dose, additional oral doses may be administered at intervals of ≥2 hours, up to a maximum oral dosage of 200 mg daily.²⁷⁴

If headache recurs after an initial sub-Q dose, additional oral doses may be administered at intervals ≥2 hours, up to a maximum oral dosage of 100 mg daily.²⁷⁴

Intranasal

5, 10, or 20 mg as a single dose; individualize dosage selection, weighing the possible benefit (greater effectiveness) and risks (increased adverse effects) of the 20-mg dose.²⁴⁹ Doses >20 mg provide no additional benefit.²⁴⁹

To achieve a 10-mg dose, administer a single 5-mg dose into each nostril.²⁴⁹

If headache recurs, dose may be repeated once after 2 hours, up to a maximum dosage of 40 mg daily.²⁴⁹

Sub-Q

≤6 mg as a single dose.¹ If dose-limiting adverse effects occur with 6-mg dose, lower doses (e.g., 4 mg) may be given.^{1 273} In patients receiving doses other than 4 or 6 mg, only the single-dose vials containing 6 mg/0.5 mL should be used to provide the desired dose.^{1 273}

If headache recurs, a 6-mg sub-Q dose may be repeated once after ≥1 hour or additional oral doses may be administered at intervals ≥2 hours, up to a maximum oral dosage of 100 mg daily.²⁷³

If patient does not respond to first 6-mg dose, additional doses are unlikely to provide benefit.^{1 2 3 6 7 8 9 174 176 181 236 237}

Cluster Headache

Sub-Q

≤6 mg as a single dose.¹ If dose-limiting adverse effects occur with 6-mg dose, lower doses may be administered using only single-dose vials; use autoinjection device only with prefilled, unit-of-use syringes containing 6 mg.¹

If headache recurs, 6-mg dose may be repeated once after ≥1 hour, up to a maximum dosage of 12 mg in any 24-hour period.¹

If patient does not respond to first 6-mg dose, additional doses are unlikely to provide benefit.^{1 2 3 6 7 8 9 174 176 181 236 237}

Prescribing Limits

Adults

Vascular Headaches

Migraine

Oral

Maximum 200 mg daily; do not exceed 100 mg daily if following an initial sub-Q dose.²⁷³

Safety of treating an average of >4 headaches per 30-day period has not been established.¹⁴⁸

Intranasal

Maximum 40 mg daily.²⁴⁹

Safety of treating an average of >4 headaches per 30-day period has not been established.²⁴⁹

Sub-Q

Maximum 6 mg as a single dose; do not exceed 12 mg (i.e., two 6-mg doses given ≥1 hour apart) in any 24-hour period.¹

Cluster Headache

Sub-Q

Maximum 6 mg as a single dose; do not exceed 12 mg (i.e., two 6-mg doses given ≥1 hour apart) in any 24-hour period.¹

Special Populations

Hepatic Impairment

Contraindicated in patients with severe hepatic impairment.^{1 148 249} Unpredictable increases in bioavailability following oraladministration in patients with hepatic impairment.¹⁴⁸ If oral therapy is deemed advisable in these patients, do not exceed 50 mg as a single dose.¹⁴⁸

Patients Receiving MAO-A Inhibitors

Concurrent or recent (within 2 weeks) use of MAO-A inhibitor and oral or intranasal sumatriptan is contraindicated;^{148 249} sub-Qsumatriptan is not generally recommended, but if concomitant use is clinically warranted, decrease sumatriptan sub-Q dosage and administer under careful medical supervision.^{1 237}

Cautions for Sumatriptan

Contraindications

• 
  

  Known or suspected ischemic heart disease (e.g., angina pectoris, MI, silent ischemia).^{1 148 249}

  
  


• 
  

  Coronary artery vasospasm (e.g., Prinzmetal variant angina).^{1 148 249}

  
  


• 
  

  Other serious underlying cardiovascular disease (e.g., uncontrolled hypertension).^{1 148 249}

  
  


• 
  

  Cerebrovascular syndromes (e.g., stroke syndrome, TIAs).^{1 148 249}

  
  


• 
  

  Peripheral vascular ischemia (e.g., ischemic bowel disease).^{1 148 249}

  
  


• 
  

  Hemiplegic or basilar migraine.^{1 148 249}

  
  


• 
  

  Treatment within previous 24 hours with another 5-HT₁ receptor agonist or an ergot alkaloid.^{1 148 249} (See Specific Drugs under Interactions.)

  
  


• 
  

  Concurrent or recent (within 2 weeks) treatment with an MAO-A inhibitor (oral and nasal sumatriptan formulations).^{1 148 249}

  
  


• 
  

  Severe hepatic impairment.^{1 148 249}

  
  


• 
  

  Known hypersensitivity to sumatriptan or any ingredient in the formulation.^{1 148 249}

  
  

Warnings/Precautions

Warnings

Use oral or intranasal sumatriptan only in patients in whom a clear diagnosis of migraine has been established.^{148 249} Use sub-Q sumatriptan only in patients in whom a clear diagnosis of migraine or cluster headache has been established.¹

Exclude other potentially serious neurologic disorders before administering sumatriptan to patients not previously diagnosed with migraine or cluster headache or to those with atypical symptoms.^{1 61 148 236 237}

Cardiac Effects

Risk of myocardial ischemia and/or infarction, coronary vasospasm, life-threatening cardiac rhythm disturbances, and death.^{1 148 249}

Use not recommended in patients with known or suspected ischemic or vasospastic heart disease or in patients in whom unrecognized CAD is likely (e.g., postmenopausal women; men >40 years of age; patients with risk factors such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, or family history of CAD) unless there is satisfactory evidence from prior cardiovascular evaluation that patient does not have CAD, ischemic heart disease, or other underlying cardiovascular disease.^{1 148 249}

Administer initial dose to patients with risk factors for CAD who have completed satisfactory cardiovascular evaluation under medical supervision (e.g., in clinician’s office, possibly followed by ECG) unless patient previously received the drug.^{1 148 249}

Periodic cardiovascular evaluation recommended in patients with risk factors for CAD if receiving intermittent long-term therapy, including patients with cluster headache (predominantly males >40 years of age).^{1 148 249}

Patients with symptoms suggestive of angina after receiving sumatriptan should be evaluated for presence of CAD or predisposition to Prinzmetal variant angina before receiving additional doses; if administration resumed and such signs or symptoms recur, ECG evaluation recommended.^{1 148 249}

Cerebrovascular Events

Possible cerebral or subarachnoid hemorrhage, stroke, and other cerebrovascular events, sometimes fatal.^{1 148 249}

Risk of certain cerebrovascular events (e.g., stroke, TIA) may be increased in patients with migraine.^{1 148 249}

Other Cardiovascular or Vasospastic Effects

Peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea reported.^{1 148 249} Further evaluation recommended if signs or symptoms of decreased arterial flow (e.g., ischemic bowel syndrome, Raynaud’s syndrome) occur following administration.^{1 6 8}

Substantial increases in BP, including hypertensive crises, reported rarely in patients with or without history of hypertension; administer with caution in patients with controlled hypertension as transient increases in BP and peripheral vascular resistance are possible.^{1 148 249} (See Contraindications under Cautions.)

Serotonin Syndrome

Potentially life-threatening serotonin syndrome reported during concurrent therapy with 5-HT₁ receptor agonists (“triptans”) and SSRIs or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs).^{272 273 274 275} Symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).^{272 273 274 275}

Local Effects

Possible transient irritation in nose and throat (e.g., burning, numbness, paresthesia, discharge, pain/soreness), sometimes severe, after intranasal administration; symptoms usually resolve in <2 hours.²⁴⁹ Effects of extended and repeated use on nasal and/or respiratory mucosa not systematically evaluated.²⁴⁹

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions (e.g., anaphylaxis/anaphylactoid reactions), possibly life-threatening or fatal, reported rarely; increased risk in patients with history of sensitivity to multiple allergens.^{1 148 249}

General Precautions

Seizures

Seizures reported rarely; use with caution in patients with a history of seizures or with conditions associated with a lowered seizure threshold.^{273 274 275}

Ocular Effects

Possible accumulation of sumatriptan and/or its metabolites in melanin-rich tissues (e.g., eye) over time, resulting in potential toxicity in these tissues with extended use.^{1 148 249}

Corneal opacities and corneal epithelial defects reported in dogs. No specific recommendations for monitoring.

Specific Populations

Pregnancy

Category C.^{1 148 249} Sumatriptan Pregnancy Registry at 800-336-2176.^{1 148 249}

Lactation

Distributed into human milk.^{1 148 249} The manufacturer recommends avoiding breast-feeding for 12 hours after receiving sumatriptan oral tablets, sub-Q injection, or nasal spray.^{273 274 275}

Pediatric Use

Safety and efficacy not established in children <18 years of age; use not recommended.^{1 148 249}

Geriatric Use

Use not recommended due to possible decreased hepatic function, potential for more pronounced increases in BP, and increased risk for CAD in geriatric patients.^{1 148 249}

Hepatic Impairment

Contraindicated in patients with severe hepatic impairment.^{1 148 249} Due to important role of the liver in presystemic clearance of oral sumatriptan, dosage adjustment recommended if oral therapy is deemed advisable in patients with hepatic impairment.¹⁴⁸ (See Special Populations under Dosage and Administration.)

Common Adverse Effects

With oral therapy, pain/pressure sensations in chest/neck/throat/jaw, paresthesia, warm or cold sensation, malaise/fatigue, vertigo.¹⁴⁸

With intranasal therapy, taste disturbances, nausea, vomiting, disorder/discomfort of nasal cavity or sinuses.²⁴⁹

With sub-Q therapy, injection site reaction, atypical sensations (e.g., tingling, warm/hot sensation, burning, feeling of heaviness, pressure, tightness, numbness), dizziness/vertigo, flushing, mouth/tongue discomfort, weakness, neck pain/stiffness, chest discomfort.¹

Interactions for Sumatriptan

Metabolized principally by MAO-A isoenzyme in vitro.¹⁴⁸

Protein-bound Drugs

Effect on protein binding of other drugs has not been evaluated,¹ but expected to be minor due to low-level protein binding of sumatriptan.^{148 249}

Specific Drugs

Drug	Interaction	Comments
Acetaminophen	Pretreatment with oral sumatriptan followed by acetaminophen affected rate, but not extent of acetaminophen absorption over 8 hours187
Alcohol	Administration of alcohol 30 minutes prior to oral sumatriptan did not affect sumatriptan pharmacokinetics44 45 148 236
Amitriptyline	Concomitant use did not affect sumatriptan efficacy1 40 62
Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and SNRIs (e.g., duloxetine, venlafaxine)	Potentially life-threatening serotonin syndrome272 273 274 275	Observe carefully if used concomitantly, particularly during treatment initiation, dosage increases, or when another serotonergic agent is initiated272 273 274 275
Ergot alkaloids (e.g., ergotamine, dihydroergotamine, methysergide)	Additive vasospastic effects1 148 249	Use within 24 hours contraindicated1 148 249
5-HT1receptor agonists	Additive vasospastic effects1 148 249	Use within 24 hours contraindicated1 148 249
MAO inhibitors	MAO-A inhibitors decrease sumatriptan clearance, resulting in substantially increased systemic exposure; no substantial effect on sumatriptan metabolism seen with an MAO-B inhibitor1 148 249	Use of nasal or oralsumatriptan within 2 weeks of MAO-A inhibitor contraindicated; although not generally recommended, if clinically warranted, sub-Q sumatriptan may be used concurrently with MAO-A inhibitors with appropriate dosage adjustment and careful monitoring1 237
Propranolol	Concomitant use did not affect sumatriptan efficacy;1 40 62 pretreatment with propranolol did not alter pharmacokinetics or pharmacodynamics of oral sumatriptan62
Verapamil	Concomitant use did not affect sumatriptan efficacy1 40 62
Xylometazoline	Topical application of xylometazoline to nasal mucosa 15 minutes prior to intranasal sumatriptan did not affect sumatriptan pharmacokinetics249

Sumatriptan Pharmacokinetics

Absorption

Bioavailability

Absorbed rapidly after oral, intranasal, or sub-Q administration, with peak plasma concentrations attained within approximately 0.5–5 hours, 0.8–1.8 hours, or 5–20 minutes, respectively.^{1 2 3 13 45 61 78 79 89 96 123 146 148 166 168 236} Bioavailability after sub-Q administration averages 97% of that obtained with IV administration^{1 44} ; bioavailability after oral or intranasal administration averages only about 15 or 17%, respectively, principally due to presystemic metabolism and in part due to incomplete absorption.^{2 13 14 44 45 61 89 146 148 166 168 249}

Oral absorption is not appreciably affected by gastric stasis that may occur during migraine attack,^{3 13 45 146} but time to peak concentration is prolonged by about 30 minutes;^{3 13 45 96 146 148} pharmacokinetics after sub-Q injection appear to be similar during migraine attacks and pain-free periods.¹

Special Populations

In patients with hepatic impairment, bioavailability after oral administration may be markedly increased.¹⁴⁸ In a small study, AUC and peak plasma concentrations increased approximately 70% and time to peak plasma concentrations occurred 40 minutes earlier after oral administration compared with such values in healthy adults.¹⁴⁸

Onset

After oral administration, onset of relief of migraine symptoms generally occurs within 1–3 hours after single doses (25–100 mg),^{92 148 162 178 191} with maximum pain relief attained within 3–6 hours.^{148 178 191}

After intranasal administration, onset of headache relief occurs within 30 minutes following a 10-, 20-, or 40-mg dose.^{123 243}

After sub-Q administration, onset of pain relief usually occurs within 10–34 minutes in patients with moderate to severe migraine headache pain, with maximum relief attained within 1–2 hours;^{1 8 9 13 47 56 162 176 181} onset of pain relief generally occurs within 4–7 minutes in patients with cluster headache, with headache resolution shortly thereafter.^{40 49 75 184}

Food

Food does not appreciably affect oral bioavailability, but prolongs time to peak concentration.^{2 13 44 148}

Distribution

Extent

Rapidly and widely distributed into body tissues after sub-Q administration.^{1 14 146 148 168}

Distributed into human milk;^{1 148} only small amounts cross placenta by passive transport in vitro.²³⁵

Plasma Protein Binding

Approximately 14–21%.^{1 14 45 148}

Elimination

Metabolism

Metabolized in the liver and possibly in the GI tract principally to inactive indole acetic acid metabolite and other minor metabolites;^{1 2 3 13 14 104 148 166} metabolized principally by MAO-A isoenzyme in vitro.^{1 37 48 148}

Elimination Route

After oral administration, excreted in urine (57–60%) and feces (37–40%); only 3 and 9% of dose is excreted as unchanged drug in urine and feces, respectively.^{14 45 148 13 45 148 166 168} After sub-Q administration, approximately 22 or 38–53% of dose is excreted in urine unchanged or as indole acetic acid metabolite, respectively;^{1 45 168} 0.6 and 3.3% of dose is excreted in feces as unchanged drug and indole acetic acid metabolite, respectively.^{2 13 14 45}

Half-life

1.5–2.6 hours.^{1 6 44 45 78 79 89 91 148 166 168 249}

Special Populations

In patients with renal impairment, pharmacokinetics not evaluated, but little clinical effect expected since drug is largely metabolized to an inactive metabolite.^{1 148 249}

Stability

Storage

Oral

Tablets

2–30°C.¹⁴⁸

Intranasal

Solution

2–30°C; protect from light.²⁴⁹

Parenteral

Injection

2–30°C; protect from light.¹

Actions

• 
  

  Binds with high affinity to 5-HT type 1-like receptors, probably 5-HT_1B and 5-HT_1D subtypes.^{1 2 3 4 5 6 7 8 223 224}

  
  


• 
  

  Precise mechanism of action not established;^{4 6 9 13 77 87} may ameliorate migraine and cluster headache through selective constriction of certain large cranial blood vessels and/or inhibition of neurogenic inflammatory processes in the CNS.^{1 2 3 6 7 9 10 13 47 66 73 77 88 110 119 131 177 184 186 217 236 237}

  
  

Advice to Patients

• 
  

  Importance of immediately informing a clinician of any tightness, pain, pressure, or heaviness in chest, throat, jaw, or neck, as well as sudden and/or severe abdominal pain, shortness of breath, wheezing, heart throbbing, facial swelling (e.g., eyelids, face, lips), rash, or hives after taking sumatriptan and of not taking sumatriptan again until evaluated by a clinician.¹

  
  


• 
  

  Importance of taking sumatriptan exactly as prescribed.^{1 148 249}

  
  


• 
  

  Importance of providing patient a copy of manufacturer’s patient information.^{1 148 249} Importance of clinician providing adequate instructions, as well as the written administration instructions supplied with the autoinjection device or nasal spray, before first use.^{1 171 249}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).^{1 148 249}

  
  


• 
  

  Importance of informing patients of risk of serotonin syndrome with concurrent use of sumatriptan and an SSRI or SNRI.^{272 273 274 275} Importance of seeking immediate medical attention if symptoms of serotonin syndrome develop.^{272 273 274 275}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 148 249}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{1 148 249} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Sumatriptan

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Nasal	Solution	5 mg/0.1 mL	Imitrex Nasal Spray	GlaxoSmithKline
		20 mg/0.1 mL	Imitrex Nasal Spray	GlaxoSmithKline

Sumatriptan Succinate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	25 mg (of sumatriptan)	Imitrex	GlaxoSmithKline
		50 mg (of sumatriptan)	Imitrex	GlaxoSmithKline
		100 mg (of sumatriptan)	Imitrex	GlaxoSmithKline
Parenteral	Injection, for sub-Q use only	4 mg/0.5 mL (of sumatriptan)	Imitrex (available in 0.5-mL [4-mg] unit-of-use syringes)	GlaxoSmithKline
		6 mg/0.5 mL (of sumatriptan)	Imitrex (available in 0.5-mL [6-mg] unit-of-use syringes and as 0.5 mL [6-mg] single-dose vials)	GlaxoSmithKline

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Imitrex 100MG Tablets (GLAXO SMITH KLINE): 9/$250.99 or 27/$743.93

Imitrex 20MG/ACT Solution (GLAXO SMITH KLINE): 6/$270.98 or 18/$790.96

Imitrex 25MG Tablets (GLAXO SMITH KLINE): 9/$272.65 or 27/$791.50

Imitrex 5MG/ACT Solution (GLAXO SMITH KLINE): 1/$55.49 or 3/$136.30

Imitrex 50MG Tablets (GLAXO SMITH KLINE): 9/$266.99 or 27/$774.99

Imitrex STATdose Refill 6MG/0.5ML Solution (GLAXO SMITH KLINE): 1/$217.16 or 3/$603.25

Imitrex STATdose System 6MG/0.5ML Solution (GLAXO SMITH KLINE): 1/$217.16 or 3/$628.59

SUMAtriptan 20MG/ACT Solution (SANDOZ): 1/$45.99 or 3/$119.96

SUMAtriptan 5MG/ACT Solution (SANDOZ): 1/$45.99 or 3/$125.97

SUMAtriptan Succinate 100MG Tablets (SUN PHARMACEUTICAL): 9/$199.97 or 27/$569.98

SUMAtriptan Succinate 25MG Tablets (SUN PHARMACEUTICAL): 9/$219.99 or 27/$619.95

SUMAtriptan Succinate 50MG Tablets (SUN PHARMACEUTICAL): 9/$199.99 or 27/$569.97

Sumavel DosePro 6MG/0.5ML Device (ZOGENIX): 1/$101.99 or 2/$291.97

Treximet 85-500MG Tablets (GLAXO SMITH KLINE): 9/$216.99 or 27/$607.99

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Glaxo Wellcome. Imitrex (sumatriptan succinate) injection prescribing information. Research Triangle Park, NC; 2001 Mar.

2. Hsu VD. Sumatriptan: a new drug for vascular headache. Clin Pharm. 1992; 11:919-29. [IDIS 303852] [PubMed 1334452]

3. Bateman DN. Sumatriptan. Lancet. 1993; 341:221-4. [IDIS 308640] [PubMed 8093509]

4. Peroutka SJ. Serotonin receptor subtypes and neuropsychiatric diseases: focus on 5-HT_1D and 5-HT₃ receptor agents. Pharmacol Rev. 1991; 43:579-86. [IDIS 296518] [PubMed 1663621]

5. MacIntyre PD, Bhargava B, Hogg KJ et al. Effect of subcutaneous sumatriptan, a selective 5HT₁ agonist, on the systemic, pulmonary, and coronary circulation. Circulation. 1993; 87:401-5. [IDIS 309421] [PubMed 8381056]

6. Fullerton T, Gengo FM. Sumatriptan: a selective 5-hydroxytryptamine receptor agonist for the acute treatment of migraine. Ann Pharmacother. 1992; 26:800-8. [IDIS 298261] [PubMed 1319244]

7. Anon. Sumatriptan for migraine. Med Lett Drugs Ther. 1992; 34:91-3. [PubMed 1326077]

8. Ferrari MD and the Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N Engl J Med. 1991; 325:316-21. [IDIS 283296] [PubMed 1647495]

9. Cady RK, Wendt JK, Kirchner JR et al. Treatment of acute migraine with subcutaneous sumatriptan. JAMA. 1991; 265:2831-5. [IDIS 281579] [PubMed 1851894]

10. Friberg L, Olesen J, Iversen HK et al. Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan. Lancet. 1991; 338:13-7. [IDIS 282832] [PubMed 1676084]

11. Fox AW, Poe TE. Use and safety of sumatriptan. Clin Pharm. 1993; 12:258. [IDIS 311529] [PubMed 8384541]

12. Glaxo, Research Triangle Park, NC: Personal communication.

13. Plosker GL, McTavish D. Sumatriptan: a reappraisal of its pharmacology and therapeutic efficacy in the acute treatment of migraine and cluster headache. Drugs. 1994; 47:622-51. [PubMed 7516861]

14. Dixon CM, Saynor DA, Andrew PD et al. Disposition of sumatriptan in laboratory animals and humans. Drug Metabol Disp. 1993; 21:761-9.

15. Dechant KL, Clissold SP. Sumatriptan: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the acute treatment of migraine and cluster headache. Drugs. 1992; 43:776-98. [PubMed 1379152]

16. D’Arcy PF. Adverse drug reaction (ADR) problems with sumatriptan. Intl Pharm J. 1992; 6:264-5.

17. D’Arcy PF. Warnings from the UK committee on safety of medicines: chest pain with sumatriptan. Intl Pharm J. 1992; 6:217-8.

18. Willett F, Curzen N, Adams J et al. Coronary vasospasm induced by subcutaneous sumatriptan. BMJ. 1992; 304:1415. [IDIS 297248] [PubMed 1320974]

19. Price LH, Charney DS, Delgado PL et al. Lithium treatment and serotoninergic function. Arch Gen Psych. 1989; 46:13-9.

20. Castle WM, Simmons VE. Coronary vasospasm and sumatriptan. BMJ. 1992; 305:117-8. [IDIS 299098] [PubMed 1322216]

21. Stricker BHC. Coronary v

Caprelsa

Pronunciation: van-DET-a-nib
Generic Name: Vandetanib
Brand Name: Caprelsa

Caprelsa may cause serious and sometimes fatal irregular heartbeat (eg, QT prolongation). Sudden deaths have been reported in patients taking Caprelsa. It is thought that serious irregular heartbeat may have contributed to these sudden deaths. Do not take Caprelsa if you have low blood potassium, calcium, or magnesium levels. Do not take it if you have a history of QT prolongation or long QT syndrome. Certain medicines may increase the risk of irregular heartbeat. Tell your doctor about any other medicines or supplements you take. Tell your doctor or seek medical care at once if irregular heartbeat or fainting occurs.

Electrocardiograms (ECGs) will be performed before and during treatment. These tests are used to check for irregular heartbeat. Be sure to keep all doctor and lab appointments.

Caprelsa is used for:

Treating certain types of medullary thyroid cancer. It may also be used for other conditions as determined by your doctor.

Caprelsa is a kinase inhibitor. It works by preventing the growth of cancer cells.

Do NOT use Caprelsa if:

• you are allergic to any ingredient in Caprelsa


• you have a history of certain types of irregular heartbeat (eg, QT prolongation, long QT syndrome, very slow heartbeat)


• you have low blood potassium, calcium, or magnesium levels; uncontrolled heart failure; moderate to severe liver problems; or active, severe bleeding


• you are coughing up blood


• you are taking a barbiturate (eg, phenobarbital), carbamazepine, dexamethasone, efavirenz, a hydantoin (eg, phenytoin), primidone, a rifamycin (eg, rifampin), or St. John's wort

Contact your doctor or health care provider right away if any of these apply to you.

Before using Caprelsa:

Some medical conditions may interact with Caprelsa. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if a member of your family has a history of QT prolongation


• if you have a history of heart problems (eg, congestive heart failure; fast, slow, or irregular heartbeat), a heart attack, liver or kidney problems, lung or breathing problems, bleeding problems, high blood pressure, or abnormal blood electrolyte (eg, calcium, potassium, magnesium) levels


• if you have an underactive thyroid or high blood levels of thyroid-stimulating hormone (TSH)


• if you have a history of seizures or you are taking medicine for seizures


• if you have skin problems, diarrhea, low white blood cell levels, low blood platelet levels, or a recent history of coughing up blood


• if you take or have taken any medicine that may increase the risk of a certain type of irregular heartbeat (prolonged QT interval). Check with your doctor or pharmacist if you are unsure if any of your medicines may increase the risk of this type of irregular heartbeat

Some MEDICINES MAY INTERACT with Caprelsa. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Antiarrhythmics (eg, amiodarone, dofetilide, procainamide), arsenic, astemizole, bepridil, chloroquine, cisapride, dasatinib, dolasetron, domperidone, droperidol, granisetron, halofantrine, haloperidol, iloperidone, ketolides (eg, telithromycin), lapatinib, macrolide antibiotics (eg, clarithromycin), maprotiline, methadone, nilotinib, paliperidone, pentamidine, phenothiazines (eg, chlorpromazine), pimozide, quinolones (eg, moxifloxacin), sunitinib, tacrolimus, terfenadine, tetrabenazine, tricyclic antidepressants (eg, imipramine), or ziprasidone because the risk of severe and possibly fatal irregular heartbeat may be increased


• Barbiturates (eg, phenobarbital), carbamazepine, dexamethasone, efavirenz, hydantoins (eg, phenytoin), primidone, rifamycins (eg, rifampin), or St. John's wort because they may decrease Caprelsa's effectiveness


• Thyroid hormones (eg, levothyroxine) because their effectiveness may be decreased by Caprelsa

This may not be a complete list of all interactions that may occur. Ask your health care provider if Caprelsa may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Caprelsa:

Use Caprelsa as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Caprelsa comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Caprelsa refilled.


• Take Caprelsa by mouth with or without food.


• Swallow Caprelsa whole. Do not break, crush, or chew before swallowing.


• If you cannot swallow Caprelsa whole, place your dose in a glass containing 2 oz (60 mL) of non-carbonated water only. Stir the mixture for about 10 minutes until the medicine is in very small pieces (the tablets will not completely dissolve). Drink all of the mixture right away. Rinse the container with an additional 4 oz (120 mL) of non-carbonated water and drink the contents to be sure that the entire dose is taken.


• If a tablet is crushed, avoid contact with it. If a crushed tablet comes into contact with your skin or your eyes, nose, lips, or mouth, wash thoroughly with water.


• Continue to take Caprelsa even if you feel well. Do not miss any doses.


• If you miss a dose of Caprelsa, take it as soon as possible. If it is within 12 hours of your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Caprelsa.

Important safety information:

• Caprelsa may cause tiredness, weakness, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Caprelsa with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do NOT take more than the recommended dose, change your dose, or stop taking Caprelsa without checking with your doctor.


• Tell your doctor or dentist that you take Caprelsa before you receive any medical or dental care, emergency care, or surgery.


• Caprelsa should usually not be used with other medicines that may increase the risk of a certain type of irregular heartbeat (prolonged QT interval). Check with your doctor or pharmacist if you are not sure if any of your medicines may increase the risk of this type of irregular heartbeat.


• Caprelsa may increase the risk of bleeding. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.


• Caprelsa may cause you to become sunburned more easily while you take it and for at least 4 months after you stop it. Avoid the sun, sunlamps, or tanning booths until you know how you react to Caprelsa. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.


• If vomiting or diarrhea occurs, you will need to take care not to become dehydrated. If you have diarrhea, you may need to take an anti-diarrheal medicine. Contact your doctor for instructions.


• Diabetes patients - Caprelsa may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Women who may become pregnant must use an effective form of birth control while taking Caprelsa and for 4 months after stopping it. If you have questions about effective birth control, talk with your doctor.


• Lab tests, including ECGs; liver, thyroid, and kidney function; blood pressure; eye exams; blood electrolyte levels; and complete blood cell counts, may be performed while you use Caprelsa. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Caprelsa should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Caprelsa may cause harm to the fetus. Do not become pregnant while you are taking it or for 4 months after you stop taking it. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of taking Caprelsa while you are pregnant. It is not known if Caprelsa is found in breast milk. Do not breast-feed while taking Caprelsa.

Possible side effects of Caprelsa:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Acne; diarrhea; dry skin; headache; loss of appetite; mild stomach pain or upset; nausea; tiredness; trouble sleeping; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thoughts or trouble thinking; black or bloody stools; blood in the urine; confusion; coughing up blood; fainting; fast or irregular heartbeat; fever, chills, or persistent sore throat; light-headedness; mental or mood changes (eg, depression); mouth sores or blisters; muscle or joint aches; numbness or weakness of the face, arm, or leg; one-sided weakness; red, swollen, blistered, or peeling skin; seizure; severe or persistent cough; severe or persistent diarrhea, dizziness, headache, tiredness, or weakness; shortness of breath or other breathing problems; slurred speech; sudden coordination problems; sudden trouble walking or balancing; sudden, unusual weight gain; swelling of the hands, feet, or ankles; tingling, pain, redness, or swelling of the palms of the hands and soles of the feet; unusual bruising or bleeding; vision changes (eg, blurred vision); vomit that looks like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Caprelsa side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include diarrhea, rash, severe headache.

Proper storage of Caprelsa:

Store Caprelsa at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Caprelsa out of the reach of children and away from pets.

General information:

• If you have any questions about Caprelsa, please talk with your doctor, pharmacist, or other health care provider.


• Caprelsa is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Caprelsa. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Caprelsa resources

• Caprelsa Side Effects (in more detail)
• Caprelsa Use in Pregnancy & Breastfeeding
• Caprelsa Drug Interactions
• Caprelsa Support Group
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• Thyroid Cancer

Gonal-F

follitropin alfa

Dosage Form: injection
Gonal-F® (follitropin alfa for injection)

For subcutaneous injection

DESCRIPTION

Gonal-F® (follitropin alfa for injection) is a human follicle stimulating hormone (FSH) preparation of recombinant DNA origin, which consists of two non-covalently linked, non-identical glycoproteins designated as the α- and β-subunits. The α- and β-subunits have 92 and 111 amino acids, respectively, and their primary and tertiary structure are indistinguishable from those of human follicle stimulating hormone.  Recombinant FSH production occurs in genetically modified Chinese Hamster Ovary (CHO) cells cultured in bioreactors.  Purification by immunochromatography using an antibody specifically binding FSH results in a highly purified preparation with a consistent FSH isoform profile, and a high specific activity.  The biological activity of follitropin alfa is determined by measuring the increase in ovary weight in female rats.  The in vivo biological activity of follitropin alfa has been calibrated against the first International Standard for Recombinant Human Follicle Stimulation Hormone established in 1995 by the Expert Committee on Biological Standards of the World Health Organization.  Gonal-F® contains no luteinizing hormone (LH) activity.  Based on available data derived from physico-chemical tests and bioassays, follitropin alfa and follitropin beta, another recombinant follicle stimulating hormone product, are indistinguishable.

Gonal-F® is a sterile, lyophilized powder intended for subcutaneous injection after reconstitution.

Each Gonal-F® Multi-Dose vial is filled with 600 IU (44 μg) or 1200 IU (87 μg) follitropin alfa to deliver 450 IU (33 μg) or 1050 IU (77 μg) follitropin alfa, respectively, and contains 30 mg sucrose, 1.11 mg dibasic sodium phosphate dihydrate and 0.45 mg monobasic sodium phosphate monohydrate.  O-phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment.  Multiple Dose vials are reconstituted with Bacteriostatic Water for Injection (0.9% benzyl alcohol), USP.

Under current storage conditions, Gonal-F® may contain up to 10% of oxidized follitropin alfa.

Therapeutic Class: Infertility

CLINICAL PHARMACOLOGY

Gonal-F® (follitropin alfa for injection) stimulates ovarian follicular growth in women who do not have primary ovarian failure.  FSH, the active component of Gonal-F® is the primary hormone responsible for follicular recruitment and development.  In order to effect final maturation of the follicle and ovulation in the absence of an endogenous LH surge, human chorionic gonadotropin (hCG) must be given following the administration of Gonal-F® when monitoring of the patient indicates that sufficient follicular development has occurred.  There is interpatient variability in response to FSH administration.  The physico-chemical, immunological, and biological activities of recombinant FSH (r-hFSH) are comparable to those of pituitary and human menopausal urine-derived FSH. Gonal-F® (follitropin alfa for injection), when administered with hCG, stimulates spermatogenesis in men with hypogonadotropic hypogonadism.  FSH, the active component of Gonal-F®, is the primary hormone responsible for spermatogenesis.

Pharmacokinetics

Single dose pharmacokinetics of follitropin alfa were determined following intravenous, subcutaneous and intramuscular administration of 150 IU Gonal-F® to 12 healthy, down-regulated female volunteers.  Steady-state pharmacokinetics were also determined in 12 healthy down-regulated female volunteers who were administered a single daily dose of 150 IU for seven days.  These pharmacokinetics were confirmed in pituitary down-regulated women undergoing in vitro fertilization and embryo transfer (IVF/ET), treated with FSH doses of up to 450 IU per day.   Additionally, single dose pharmacokinetics of follitropin alfa were determined following subcutaneous administration of 225 IU Gonal-F® to 12 healthy adult male volunteers in a cross-over design. Steady state pharmacokinetics were also determined in 6 healthy adult male volunteers who were administered a single daily dose of 225 IU Gonal-F® for 7 days.  No significant difference in pharmacokinetics is expected in males versus females when administered Gonal-F® subcutaneously. The pharmacokinetic parameters from these studies are included in Table 1.

Table 1: Pharmacokinetic parameters (mean ± SD) of FSH following administration of Gonal-F®

Population	Female				Male
	Healthy Female Volunteers			IVF/ET Patients	Healthy Male Volunteers
Dose (IU)	Single Dose IM	Single Dose SC	Multiple Dose SC	Multiple Dose SC	Single Dose SC	Multiple Dose SC
	(150 IU)	(150 IU)	(7 x 150 IU)	(5 x 225 IU)*	(225 IU)	(7 x 225 IU)
Abbreviations are: IVF/ET: in vitro fertilization/embryo transfer;
Cmax: peak concentration (above baseline);
tmax : time of Cmax;
CL/F: apparent clearance;
V/F: apparent volume of distribution; calculated using a one-compartment model.
t½: absorption half-life;
F: bioavailability compared to IV
# Steady-state AUC144-168 (After the 7th daily SC dose)
* First five days of fixed regimen followed by adjustment of the dose depending on response
** increases with body mass index
AUC  (IU-hr/L)	206 ± 66	176 ± 87	187 ± 61#	---	220 ± 109	186 ± 23#
Cmax (IU/L)	3 ± 1	3 ± 1	9 ± 3	---	2.5 ± 0.8	8.3 ± 0.9
tmax (hr)	25 ± 10	16 ± 10	8 ± 6	---	20 ± 14	10.7 ± 6.7
t½ terminal (hr)	50 ± 27	24 ± 11	24 ± 8	32**	41 ± 14	32 ± 4
CL/F (L/hr)	---	---	---	0.7 ± 0.2	0.86 ± 0.48	0.90 ± 0.12
V/F (L)	---	---	---	10 ± 3	---	---
F (%)	76 ± 30	66 ± 39	---	---	---	---

Absorption

The absorption rate of Gonal-F® following subcutaneous or intramuscular administration was found to be slower than the elimination rate.  Hence the pharmacokinetics of Gonal-F® are absorption rate-limited.

Distribution

Human tissue or organ distribution of FSH has not been determined for Gonal-F®.

After intravenous administration to pituitary down-regulated, healthy female volunteers, the serum profile of FSH appears to be described by a two compartment open model with a distribution half-life of about 2-2.5 hours.  Steady-state serum levels were reached after 4 to 5 days of daily administration.

Metabolism/Excretion

FSH metabolism following administration of Gonal-F® has not been studied in humans. Total clearance after IV administration in healthy females was 0.6 L/hr; mean residence time was 17-20 hours.  FSH renal clearance was 0.07 L/hr after intravenous administration representing approximately 1/8 of total clearance.

Pharmacodynamics

Following daily subcutaneous administration of 150 IU of Gonal-F® for 7 days in healthy female volunteers, serum inhibin and estradiol, and total follicular volume responded as a function of time, with pronounced inter-individual variability.  Pharmacodynamic effect lagged behind FSH serum concentration.  Of the three pharmacodynamic parameters, serum inhibin levels responded with the least delay and declined rapidly after discontinuation of Gonal-F®. Follicular growth was most delayed and continued even after discontinuation of Gonal-F® administration, and after serum FSH levels had declined.  Maximum follicular volume was better correlated with either inhibin or estradiol peak levels than with FSH concentration.  Inhibin rise was an early index of follicular development.  In healthy male volunteers, despite high interindividual variation and the absence of down-regulation, daily administration of 225 IU Gonal-F® was shown to increase the levels of inhibin to reach a plateau during the whole administration period and then return to baseline.

Population pharmacokinetics and pharmacodynamics

To establish the pharmacokinetics and pharmacodynamics of FSH in a target population, measurements performed during a clinical study of in vitro fertilization/embryo transfer were used in conjunction with pharmacokinetic data from studies in healthy female volunteers. The apparent clearance was comparable to that in healthy volunteers.  The absorption rate was found to be influenced by the body mass index (BMI), suggesting that the higher the BMI, the lower the rate of absorption.  However, FSH serum levels following fixed (during the first five days) and then adjusted doses of Gonal-F® were found to be poor predictors of follicular growth rate.  High pre-treatment serum FSH levels may predict lower follicular growth rates.

Special populations:  Safety, efficacy, and pharmacokinetics of Gonal-F® in patients with renal or hepatic insufficiency have not been established.

Drug-Drug Interactions:  No drug-drug interaction studies have been conducted (see PRECAUTIONS).

Clinical Studies:

Women:

The safety and efficacy of Gonal-F® have been examined in four clinical studies, two studies for ovulation induction and two studies for assisted reproductive technologies (ART).  In these comparative studies, there were no clinically significant differences between treatment groups in study outcomes.

1. Ovulation Induction:

The safety and efficacy of Gonal-F® administered subcutaneously vs. urofollitropin administered intramuscularly were assessed in a phase III, open-label, randomized, comparative, multinational, multicenter study in oligo-anovulatory infertile women who failed to ovulate or conceive following adequate clomiphene citrate therapy (Study 5642).

The primary efficacy parameter was the ovulation rate.  Two hundred and  twenty-two patients entered into the first cycle of treatment, of whom 110 received Gonal-F® and 112 received urofollitropin.  Ovulation rates were similar between Gonal-F® and urofollitropin treatment groups.  The study results for the 222 patients who received treatment in at least one cycle are summarized in Table 2.

Table 2: Cumulative Patient Ovulation and Clinical Pregnancy Rates by Treatment Group in Ovulation Induction

Study 5642			Gonal-F® (n=110)	Urofollitropin (n=112)
* A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration.
Cumulative Ovulation Rate
		Cycle 1	64%	59%
		Cycle 2	78%	82%
		Cycle 3	84%	91%
Cumulative Clinical Pregnancy*  Rate
	Cycle 1		21%	21%
	Cycle 2		28%	38%
	Cycle 3		35%	46%

For the 90 patients who had a clinical pregnancy (39 in Gonal-F® group; 51 in urofollitropin group), the outcome of the pregnancy was:

Table 3: Pregnancy Outcome by Treatment Group in Ovulation Induction

Study 5642	Gonal-F® (n=39)	Urofollitropin  (n=51)
Pregnancies not reaching term	20.5%	13.7%
Single births	74.4%	74.5%
Multiple births	5.1%	11.8%

A second  randomized, comparative, open-label, multicenter study was conducted in 23 U.S. centers (Study 5727).  The primary efficacy parameter was ovulation rate.  Ovulation rates were similar between Gonal-F® and urofollitropin treatment groups.  Two hundred and thirty-two patients with oligo-anovulatory infertility received treatment with up to three cycles of Gonal-F® administered subcutaneously (118 patients) or urofollitropin administered intramuscularly (114 patients).

The cumulative patient ovulation rate and clinical pregnancy rates by cycle are presented for the 232 patients who received treatment in at least one cycle.

Table 4: Cumulative Patient Ovulation and Clinical Pregnancy Rates by Treatment Group in Ovulation Induction

Study 5727			Gonal-F® (n=118)	Urofollitropin (n=114)
* A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration.
Cumulative Ovulation Rate
		Cycle 1	58%	68%
		Cycle 2	72%	86%
		Cycle 3	81%	93%
Cumulative Clinical Pregnancy* Rate
	Cycle 1		13%	14%
	Cycle 2		25%	25%
	Cycle 3		37%	36%

For the 85 patients who had a clinical pregnancy (44 in Gonal-F® group; 41 in urofollitropin group), the outcome of the pregnancy is shown in Table 5.

Table 5: Pregnancy Outcome by Treatment Group in Ovulation Induction

Study 5727	Gonal-F® (n=44)	Urofollitropin (n=41)
Pregnancies not reaching term	22.7%	22.0%
Single births	63.6%	65.9%
Multiple births	13.7%	12.2%

2. Assisted Reproductive Technologies (ART):

The safety and efficacy of Gonal-F® administered subcutaneously vs. urofollitropin administered intramuscularly were assessed in a phase III, open-label, randomized, comparative, multinational, multicenter study in ovulatory, infertile women undergoing stimulation of multiple follicles for In Vitro Fertilization and Embryo Transfer (IVF/ET) after pituitary down-regulation with a GnRH agonist (Study 5503).  The purpose of the study was to demonstrate that Gonal-F®, administered subcutaneously, was clinically not different in terms of safety and efficacy from urofollitropin, administered intramuscularly.  The initial and maximal doses of Gonal-F® were 225 and 450 IU, respectively.  The primary efficacy parameter was the number of mature pre-ovulatory follicles on the day of hCG administration.  One hundred and twenty-three patients were randomized and received either Gonal-F® (60 patients) or urofollitropin (63 patients).

The results summarized in Table 6 are mean data with Gonal-F® and urofollitropin administered to ovulatory infertile women undergoing multiple follicular development for IVF/ET.

Table 6: Treatment Outcomes by Treatment Group in ART

Study 5503	Gonal-F® (n=60)	Urofollitropin (n=63)
*  A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration.
Mean number of follicles ≥ 14mm diameter on day of hCG	7.8	9.2
Mean number of oocytes recovered per patient	9.3	10.7
Mean Serum E2 (pg/mL) on day of hCG	1576	2193
Mean treatment duration in days (range)	9.9 (5-20)	9.4 (5-14)
Clinical pregnancy* rate per attempt	20%	16%
Clinical pregnancy* rate per embryo transfer	24%	19%

For the 22 patients who had a clinical pregnancy (12 in Gonal-F® group; 10 in urofollitropin group), the outcome of the pregnancy is shown in Table 7.

Table 7: Pregnancy Outcome by Treatment Group in ART

Study 5503	Gonal-F® (n=12)	Urofollitropin (n=10)
Pregnancies not reaching term	25.0%	20.0%
Single births	41.7%	50.0%
Multiple births	33.3%	30.0%

A second randomized, comparative, open-label, multicenter study was conducted in 7 U.S. centers (Study 5533). One hundred and fourteen patients with ovulatory infertility undergoing IVF/ET were randomized and received either Gonal-F® by subcutaneous administration (56 patients) or urofollitropin by intramuscular administration (58 patients) following pituitary down-regulation with a GnRH agonist.  The primary efficacy parameter was the number of mature pre-ovulatory follicles on the day of hCG administration.  Results are summarized in Table 8.

Table 8: Treatment Outcomes by Treatment Group in ART

Study 5533	Gonal-F® (n=56)	urofollitropin (n=58)
*  A clinical pregnancy was defined as a pregnancy during which a fetal sac (with or without heart activity) was visualized by ultrasound on day 34-36 after hCG administration.
Mean number of follicles ≥ 14mm diameter on day of hCG	7.2	8.3
Mean number of oocytes recovered per patient	9.3	12.3
Mean Serum E2 (pg/mL) on day of hCG	1236	1513
Mean treatment duration in days (range)	10.1(5-15)	9.0 (5-12)
Clinical pregnancy* rate per attempt	21%	22%
Clinical pregnancy* rate per embryo transfer	26%	25%

For the 25 patients who had a clinical pregnancy (12 in Gonal-F® group; 13 in urofollitropin group), the outcome of the pregnancy is shown in Table 9.

Table 9:  Pregnancy Outcome by Treatment Group in ART

Study 5533	Gonal-F® (n=12)	Urofollitropin (n=13)
Pregnancies not reaching term	33.3%	30.8%
Single births	41.7%	38.5%
Multiple births	25.0%	30.8%

Men:

The safety and efficacy of Gonal-F® administered concomitantly with hCG have been examined in three open-label clinical studies for induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism.

The three multicenter studies involved three to six months of pretreatment with chorionic gonadotropin for injection (Profasi®) to normalize serum testosterone levels, followed by 18 months of treatment with Gonal-F® and hCG.  The objective of each study was induction of spermatogenesis (a sperm density of ≥ 1.5 x 106/mL).

Study 5844 enrolled 32 patients in six centers in the United Kingdom, France and Germany.  The second trial, Study 6410, was conducted in Australia and enrolled 10 patients in two centers.  Study 6793, conducted in 7 centers in the United States, was planned to enroll 32 patients.  The interim data for the US study includes 30 of the planned 32 patients. For all 3 studies, a total of 72 patients were enrolled and received hCG and 56 of those patients entered the Gonal-F® treatment phase of the trials.

The populations enrolled in the three studies were similar: Study 5844 studied a naïve population who had had no prior treatment with gonadotropins; mean age was 25.9 (range 16 to 48) years, mean (± SD) testis volume was 2.0 ± 1.2 mL, and 12 of the 32 patients (37.5%) were anosmic.  Thirty-one of the patients were Caucasian and one was Asian.  In Study 6410, mean age was 36 (range 26 to 48) years, 6 and 1 of the 10 patients had previously been treated with gonadotropins and GnRH, respectively; mean testis volume was 4.5 ± 2.9 mL; and 2 of the 10 patients (20%) were anosmic.  Seven patients were Caucasian and three were Asian.  In the 30 patients reported in the interim analysis of Study 6793, the mean age was 30.1 (range 22 to 44) years; 4 and 3 of the 30 patients had been treated with gonadotropins and GnRH, respectively, in the past; mean testis volume was 4.4 ± 1.3 mL; and 10 of  the 30 patients (33.3%) were anosmic. Twenty five of the patients were Caucasian, three were Asian, and one each of Moroccan and Indian ancestry.

The primary efficacy endpoint of all three studies was the achievement of a sperm density ≥ 1.5 x 106/mL.  The study results for the patients treated with Gonal-F® and hCG are summarized in Table 10.

Table 10: Number of Men Receiving Gonal-F® Who Achieved a Sperm Density ≥1.5 x 106/mL

			Study 5844 (n=26)	Study 6410 (n=8)	Study 6793 (n=22) *
* Interim data
Sperm Concentration ≥ 1.5 x 106/mL
		Yes	12 (46.2%)	5 (62.5%)	14 (63.6%)
		No	14 (53.8%)	3 (37.5%)	8 (36.4%)
	95% Confidence Interval		(26.6% - 66.6%)	(24.5% - 91.5%)	(40.7% - 82.8%)

The time to achievement of the primary efficacy endpoint is summarized in Table 11.

Table 11: Time to Achievement of Sperm Density ≥1.5 x 106/mL in Men Receiving Gonal-F®

		Study 5844 (n=26)	Study 6410 (n=8)	Study 6793 (n=22) *
* Interim data
Number of Men Achieving Sperm Concentration
	n	12	5	14
	Time (Months) to Sperm
	Concentration ≥ 1.5 x 106/mL
	Median	12.4	9.1	6.8
	Range	(2.7 – 18.1)	(8.8 – 11.7)	(2.8 – 15.7)

Table 12: Pregnancy Outcome in Partners of Men Desiring Fertility

	Study 5844 (n=7)	Study 6410 (n=10)	Study 6793 (n=20) *
* Interim data
Pregnancy	6 (86%)	3 (30%)	3 (15%)
Pregnancy not reaching term	1 (14%)	1 (10%)	2 (10%)
Single births	5 (71%)	2 (20%)	1 (5%)

Of the 56 patients who received Gonal-F® in Studies 5844, 6410, and 6793, 12 pregnancies were achieved in 10 partners of the 37 patients who were seeking pregnancy and who currently had a partner during the studies.  Thus, pregnancy (clinical and chemical)  was documented to have been achieved by 27% of the patients’ partners seeking pregnancy during the exposure period to Gonal-F® in the 3 trials.  Eight pregnancies continued to term, and 8 healthy babies were born to 7 couples as a result of those studies.

INDICATIONS AND USAGE

Women:  Gonal-F® (follitropin alfa for injection) is indicated for the induction of ovulation and pregnancy in the anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure.  Gonal-F® is also indicated for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program.

Selection of Patients:

1. Before treatment with Gonal-F® is instituted, a thorough gynecologic and endocrinologic evaluation must be performed.  This should include an assessment of pelvic anatomy.  Patients with tubal obstruction should receive Gonal-F® only if enrolled in an in vitro fertilization program.


2. Primary ovarian failure should be excluded by the determination of gonadotropin levels.


3. Appropriate evaluation should be performed to exclude pregnancy.


4. Patients in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders.  A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting Gonal-F® therapy.


5. Evaluation of the partner’s fertility potential should be included in the initial evaluation.

Men:

Gonal-F® (follitropin alfa for injection) is indicated for the induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism  in whom the cause of infertility is not due to primary testicular failure.

Selection of Patients:

1. Before treatment with Gonal-F® is instituted for azoospermia, a thorough medical and endocrinologic evaluation must be performed.


2. Hypogonadotropic hypogonadism should be confirmed, and primary testicular failure should be excluded by the determination of gonadotropin levels.


3. Prior to Gonal-F® therapy for azoospermia in patients with hypogonadotropic hypogonadism, serum testosterone levels should be normalized.

CONTRAINDICATIONS

Gonal-F® (follitropin alfa for injection) is contraindicated in women and men who exhibit:

1. Prior hypersensitivity to recombinant FSH preparations or one of their excipients.


2. High levels of FSH indicating primary gonadal failure.


3. Uncontrolled thyroid or adrenal dysfunction.


4. Sex hormone dependent tumors of the reproductive tract and accessory organs.


5. An organic intracranial lesion such as a pituitary tumor.
   

   And in women who exhibit:

   
   


6. Abnormal uterine bleeding of undetermined origin (see "Selection of Patients").


7. Ovarian cyst or enlargement of undetermined origin (see "Selection of Patients").


8. Pregnancy.

WARNINGS

Gonal-F® (follitropin alfa for injection) should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Gonal-F® is a potent gonadotropic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) in women with or without pulmonary or vascular complications.  Gonadotropin therapy requires a certain time commitment by physicians and supportive health professionals, and requires the availability of appropriate monitoring facilities (see "Precautions / Laboratory Tests").  Safe and effective use of Gonal-F® in women requires monitoring of ovarian response with serum estradiol and vaginal ultrasound on a regular basis.  The lowest effective dose should be used.

Overstimulation of the Ovary During FSH Therapy:

Ovarian Enlargement: Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distention and/or abdominal pain occurs in approximately 20% of those treated with urofollitropin and hCG, and generally regresses without treatment within two or three weeks.  Careful monitoring of ovarian response can further minimize the risk of overstimulation.

If the ovaries are abnormally enlarged on the last day of Gonal-F® therapy, hCG should not be administered in this course of therapy.  This will reduce the chances of development of  Ovarian Hyperstimulation Syndrome.

Ovarian Hyperstimulation Syndrome (OHSS): OHSS is a medical event distinct from uncomplicated ovarian enlargement.  Severe OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event.  It is characterized by an apparent dramatic increase in vascular permeability which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium.  The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain.  The following symptomatology has been seen with cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhea, severe ovarian enlargement, weight gain, dyspnea, and oliguria.  Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events (see "Pulmonary and Vascular Complications").  Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with Ovarian Hyperstimulation Syndrome (OHSS).

OHSS occurred in 9 of 228 (3.9%) Gonal-F® treated women during ovulation induction clinical trials and of this number, 1 of 228 (0.4%) was classified as severe.  In ART clinical studies, OHSS occurred in 0 of 116 (0.0%) Gonal-F® treated women.  OHSS may be more severe and more protracted if pregnancy occurs.  OHSS develops rapidly; therefore, patients should be followed for at least two weeks after hCG administration.  Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about seven to ten days following treatment.  Usually, OHSS resolves spontaneously with the onset of menses.  If there is evidence that OHSS may be developing prior to hCG administration (see "Precautions / Laboratory Tests"), the hCG must be withheld.

If severe OHSS occurs, treatment must be stopped and the patient should be hospitalized.

A physician experienced in the management of this syndrome, or who is experienced in the management of fluid and electrolyte imbalances should be consulted.

Pulmonary and Vascular Complications:

Serious pulmonary conditions (e.g., atelectasis, acute respiratory distress syndrome and exacerbation of asthma) have been reported.  In addition, thromboembolic events both in association with, and separate from Ovarian Hyperstimulation Syndrome have been reported.  Intravascular thrombosis and embolism can result in reduced blood flow to critical organs or the extremities.  Sequelae of such events have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), and arterial occlusion resulting in loss of limb.  In rare cases, pulmonary complications and/or thromboembolic events have resulted in death.

Multiple Births:

Reports of multiple births have been associated with  Gonal-F® treatment.  In ovulation induction clinical trials, 12.3% of live births were multiple births in women receiving Gonal-F® and 14.5% of live births were multiple births in women receiving urofollitropin. In IVF/ET clinical trials, 44.0% of live births were multiple births in women receiving Gonal-F® and 41.0% of live births were multiple births in women receiving urofollitropin and is dependent on the number of embryos transferred.  The patient should be advised of the potential risk of multiple births before starting treatment.

PRECAUTIONS

General:

Careful attention should be given to the diagnosis of infertility in candidates for Gonal-F® (follitropin alfa for injection) therapy (see "Indications and Usage / Selection of Patients").

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