ioflupane I-123

Generic Name: ioflupane I-123 (EYE oh FLOO payne)

Brand Names: DaTscan

What is ioflupane I-123?

Ioflupane I-123 is in a group of drugs called diagnostic radiopharmaceuticals.(RAY dee oh far ma SOO tik als). Ioflupane I-123 is a radioactive agent that alows images of the brain to be detected by a gamma camera.

Ioflupane I-123 is used to detect brain signs of Parkinson's disease in people with symptoms such as tremors, loss of balance or coordination, shuffling walk, or other movement problems.

Ioflupane I-123 may also be used for purposes not listed in this medication guide.

What is the most important information I should know about ioflupane I-123?

You should not receive this medication if you are allergic to ioflupane. Tell your doctor if you have ever had any type of reaction to another contrast agent, or to iodine.

Before you receive ioflupane I-123, tell your doctor if you have kidney or liver disease, or a thyroid disorder.

Drink plenty of liquid before you receive ioflupane I-123, and for at least 48 hours afterward. Follow your doctor's instructions about the types and amount of liquids you should drink before and after your test. Ioflupane I-123 is radioactive and it can cause dangerous effects on your bladder if it is not properly eliminated from your body through urination. Do not allow yourself to become dehydrated during the first few days after receiving ioflupane I-123. Call your doctor if you have any vomiting or diarrhea during this time. Follow your doctor's instructions about the type and amount of liquids you should drink.

What should I discuss with my healthcare provider before receiving ioflupane I-123?

You should not receive this medication if you are allergic to ioflupane. Tell your doctor if you have ever had any type of reaction to another contrast agent, or to iodine.

To make sure you can safely receive ioflupane I-123, tell your doctor if you have any of these other conditions:

• 
  

  kidney disease;

  
  


• 
  

  liver disease; or

  
  


• 
  

  a thyroid disorder.

  
  

FDA pregnancy category C. It is not known whether ioflupane I-123 will harm an unborn baby. Tell your doctor if you are pregnant before receiving this medication. It is not known whether ioflupane I-123 passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are receiving ioflupane I-123. Older adults may need kidney function tests before receiving ioflupane I-123. Your kidney function may also need to be watched closely after you have received this medication.

How is ioflupane I-123 given?

Ioflupane I-123 is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. It is usually given about 3 to 6 hours before your radiologic test.

At least 1 hour before you are treated with ioflupane I-123, you will be given a liquid drink that contains medicine to protect your thyroid from harmful radioactive effects of ioflupane I-123.

Drink plenty of liquid before you receive ioflupane I-123, and for at least 48 hours afterward. Follow your doctor's instructions about the types and amount of liquids you should drink before and after your test. Ioflupane I-123 is radioactive and it can cause dangerous effects on your bladder if it is not properly eliminated from your body through urination.

Expect to urinate often during the first 48 hours after your test. You will know you are getting enough extra fluid if you are urinating more than usual during this time. Urinating often will help rid your body of the radioactive iodine.

What happens if I miss a dose?

Since ioflupane I-123 is used only given once before your radiologic test, you will not be on a daily dosing schedule. Call your doctor if for some reason you will not be able to complete your radiologic test within 3 to 6 hours after you receive your injection.

What happens if I overdose?

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

What should I avoid after receiving ioflupane I-123?

Do not allow yourself to become dehydrated during the first few days after receiving ioflupane I-123. Call your doctor if you have any vomiting or diarrhea during this time. Follow your doctor's instructions about the type and amount of liquids you should drink.

Ioflupane I-123 side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Less serious side effects may include:

• 
  

  pain, swelling, burning, or irritation around the IV needle;

  
  


• 
  

  headache;

  
  


• 
  

  dizziness, spinning sensation;

  
  


• 
  

  dry mouth; or

  
  


• 
  

  nausea.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Ioflupane I-123 Dosing Information

Usual Adult Dose for Computed Tomography:

For striatal dopamine transporter visualization using single photon emission computed tomography (SPECT) brain imaging:

111 to 185 MBq (3 to 5 mCi) administered intravenously

What other drugs will affect ioflupane I-123?

You may need to stop using certain drugs for a short time before you receive ioflupane I-123. Tell your doctor about all other medicines you use, especially:

• 
  

  benztropine (Cogentin);

  
  


• 
  

  buspirone (BuSpar);

  
  


• 
  

  selegiline (Eldepryl, Emsam, Zelapar);

  
  


• 
  

  an antidepressant such as amoxapine (Asendin), bupropion (Wellbutrin, Zyban), sertraline (Zoloft), citalopram (Celexa), or paroxetine (Paxil);

  
  


• 
  

  decongestant cold medicines, diet pills, and other stimulants;

  
  


• 
  

  medication to treat ADHD (attention deficit hyperactivity disorder) such as Adderall, Ritalin, Concerta, and others; or

  
  


• 
  

  street drugs, especially cocaine, ecstasy, or methamphetamine.

  
  

This list is not complete and other drugs may interact with ioflupane I-123. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More ioflupane I-123 resources

• Ioflupane I-123 Side Effects (in more detail)
• Ioflupane I-123 Dosage
• Ioflupane I-123 Use in Pregnancy & Breastfeeding
• Ioflupane I-123 Drug Interactions
• Ioflupane I-123 Support Group
• 0 Reviews for Ioflupane I-123 - Add your own review/rating

• DaTscan Prescribing Information (FDA)


• DaTscan Advanced Consumer (Micromedex) - Includes Dosage Information


• DaTscan Consumer Overview

Compare ioflupane I-123 with other medications

• Computed Tomography
• Diagnosis and Investigation

Where can I get more information?

• Your doctor or pharmacist can provide more information about ioflupane I-123.

See also: ioflupane I-123 side effects (in more detail)

Ivermectin

Class: Anthelmintics
VA Class: AP200
Chemical Name: A mixture of Ivermectin Component B1a ((2aE,4E,8E) - (5′S,6S,6′R,7S,11R,13R,15S,17aR,20R,20aR,20bS) - 6′ - (S) - sec - butyl - 3′,4′,5′,6,6′,7,10,11,14,15,17a,20,20a,20b - tetradecahydro - 20,20b - dihydroxy - 5′,6,8,19 - tetramethyl - 17 - oxospiro[11,15 - methano - 2H,13H,17H - furo[4,3,2 - pq][2,6] - benzodioxacyclooctadecin - 13,2′ - [2H]pyran] - 7 - yl - 2,6 - dideoxy - 4 - O - (2,6 - dideoxy - 3 - O - methyl - α - l - arabino - hexopyranosyl) - 3 - O - methyl - α - l - arabino - hexopyranoside) and Ivermectin Component B1b ((2aE,4E,8E) - (5′S,6S,6′R,7S,11R,13R,15S,17aR,20R,20aR,20bS) - 3′,4′,5′,6,6′,7,10,11,14,15,17a,20,20a,20b - tetradecahydro - 20,20b - dihydroxy - 6′ - isopropyl - 5′,6,8,19 - tetramethyl - 17 - oxospiro[11,15 - methano - 2H,13H,17H - furo[4,3,2 - pq][2,6] - benzodioxacyclooctadecin - 13,2′ - [2H]pyran] - 7 - yl - 2,6 - dideoxy - 4 - O - (2,6 - dideoxy - 3 - O - methyl - α - l - arabino - hexopyranosyl) - 3 - O - methyl - α - l - arabino - hexopyranoside)
Molecular Formula: A mixture of Ivermectin Component B_1a (C₄₈H₇₄O₁₄) and Ivermectin Component B_1b (C₄₇H₇₂O₁₄)
CAS Number: 70288-86-7
Brands: Stromectol

Introduction

Anthelmintic and anti-ectoparasitic agent; avermectin derivative.^{1 4 6 14 15 18 19 33 45}

Uses for Ivermectin

Ascariasis

Treatment of ascariasis† caused by Ascaris lumbricoides.^{3 96} Albendazole and mebendazole are drugs of choice.^{3 80} Ivermectin also recommended as a drug of choice,³ but efficacy not clearly established.⁸⁰

Filariasis

Treatment of onchocerciasis (filariasis caused by Onchocerca volvulus; commonly referred to as river blindness).^{1 2 3 6 8 17 20 21 22 42 110} Drug of choice.^{1 2 3 6 8 17 20 21 22 42} Used in individual patients and in mass treatment and control programs.^{4 5 6 7 11 16 17 19 110} Does not kill adult O. volvulus worms, but decreases microfilarial load in skin for approximately 6–12 months following a single dose.^{1 2 8 11 18 20 80}

Treatment of filariasis caused by Mansonella streptocerca†.^{3 21} Diethylcarbamazine (available in the US from CDC) and ivermectin are drugs of choice.^{3 21} Diethylcarbamazine is potentially curative since it is active against both adult worms and microfilariae; ivermectin is effective only against microfilariae.^{3 21 22}

Has been used for treatment of filariasis caused by M. ozzardi†.^{3 23}

Treatment of filariasis caused by Wuchereria bancrofti† or Brugia malayi†; used alone or in conjunction with albendazole or diethylcarbamazine.^{2 3 4 19 63 64 65 76 77 80 90} Ivermectin does not kill adult worms, but may play an important role in mass treatment programs to suppress microfilaremia and thereby interrupt transmission in endemic areas.^{80 90} Diethylcarbamazine is usual drug of choice,^{2 3} especially for individual patients when the goal is to kill the adult worm.^{80 81 82 83 90}

Has been used in conjunction with albendazole to treat co-infection with W. bancrofti† and O. volvulus.⁷⁶

Has been used to reduce microfilaremia in the treatment of loiasis caused by Loa loa†.^{3 8 35 67} Generally not recommended since rapid killing of microfilariae increases risk of encephalopathy.³ (See Encephalopathy Risk in Onchocerciasis and Loiasis under Cautions.) Drug of choice for loiasis is diethylcarbamazine;^{3 80} preferred alternative is albendazole since it has a slower onset of action and decreased risk of encephalopathy compared with ivermectin.³

Gnathostomiasis

Treatment of gnathostomiasis† caused by Gnathostoma spinigerum.³ Drug of choice (with or without surgical removal) is albendazole or ivermectin.³

Hookworm Infections

Treatment of cutaneous larva migrans† (creeping eruption) caused by Ancylostoma braziliense (dog and cat hookworm) or Ancylostoma caninum (dog hookworm).^{2 3 15 50 69} Usually self-limited with spontaneous cure after several weeks or months;^{3 15 50 69} when treatment is indicated, drug of choice is albendazole or ivermectin^{15 50 69} and alternative is topical thiabendazole (topical preparations not commercially available in the US).³

Do not use for treatment of intestinal hookworm infections caused by Ancylostoma duodenale or Necator americanus.^{13 35 70 71 80} Appears to have little or no activity against these hookworms.^{13 35 70 71 80} Albendazole, mebendazole, and pyrantel pamoate are drugs of choice.³

Strongyloidiasis

Treatment of intestinal (i.e., nondisseminated) strongyloidiasis caused by Strongyloides stercoralis.^{1 2 3} Drug of choice;³ alternatives are albendazole and thiabendazole.³

Has been used for treatment of strongyloidiasis hyperinfection syndrome† and for treatment of strongyloidiasis in immunocompromised patients.^{2 3 98} Repeated, prolonged, or use of other drugs may be necessary in these situations;^{2 3 98} treatment failures reported.¹⁰²

Empiric treatment of strongyloidiasis before transplantation to prevent hyperinfection in hematopoietic stem cell transplant (HSCT) recipients†.⁹ Such treatment recommended by CDC, IDSA, and ASBMT in HSCT candidates with positive strongyloidiasis screening tests and those with possible exposure (e.g., unexplained eosinophilia and travel or residence history suggestive of S. stercoralis exposure [even if seronegative or stool-negative]).⁹ Data insufficient to recommend prophylaxis after HSCT to prevent recurrence of strongyloidiasis in such patients.⁹

Trichuriasis

Treatment of trichuriasis† caused by Trichuris trichiura (whipworm).^{3 96} Mebendazole is drug of choice; alternatives are albendazole and ivermectin.³

Pediculosis

Treatment of pediculosis capitis† (head lice infestation).^{3 4 14 57 62} AAP and others usually recommend topical permethrin 1% as drug of choice and topical malathion 0.5% when permethrin resistance is suspected.^{3 57 62} Ivermectin also may be a drug of choice because of ease of use and efficacy⁸⁰ or may be reserved for when there is no response to topical agents.^{13 80}

Alternative for treatment of pediculosis pubis† (pubic lice infestation).^{3 10} Drug of choice is topical permethrin 1% or topical pyrethrins with piperonyl butoxide.^{2 10}

Alternative for treatment of pediculosis corporis† (body lice infestation).¹⁰⁷ In some cases, body louse infestations may be treated by improved hygiene and by decontaminating clothes and bedding by washing at temperatures that kill lice.^{2 107} If the infestation is severe, a pediculicide also should be used (e.g., topical permethrin, topical pyrethrins with piperonyl butoxide, topical malathion, oral ivermectin).^{106 107}

Scabies

Treatment of scabies† (mite infestation).^{3 4 10 32 46 47 52 53 57 68 108 109} CDC, AAP, and others usually recommend topical permethrin 5% as scabicide of choice;^{2 10 53 57 105} CDC also recommends ivermectin as a drug of choice.¹⁰

Ivermectin may be particularly useful in refractory scabies infestations, for control of outbreaks in institutions, and when compliance with topical therapy is difficult.^{10 32 46 47 52 53 57 68 108 109}

Has been used for treatment of severe or crusted (Norwegian) scabies†.^{2 3 10 108 109} May be a drug of choice in immunocompromised patients^{3 10 52 57 100 108 109} or may be reserved for refractory infections or when topical therapy is not tolerated.^{2 3} Aggressive treatment (multiple-dose ivermectin regimen or concomitant use with a topical scabicide) may be necessary.^{10 108 109}

Ivermectin Dosage and Administration

General

Onchocerciasis

• 
  

  Does not kill adult O. volvulus worms, but may decrease microfilarial load in skin for approximately 6–12 months following a single dose.^{1 2 8 11 18 20 80 110} Follow-up and retreatment required since adult female worms continue to produce microfilaria for 9–15 years.^{5 7 19}

  
  


• 
  

  Recommendations for retreatment intervals vary.^{1 80} For individual patients, retreatment once every 6–12 months until asymptomatic has been recommended;^{2 3} intervals as short as 3 months can be considered.¹ When used in mass treatment and control programs, retreatment often given at 12-month intervals; in some programs, patients may be routinely retreated before 12 months if symptoms of pruritus develop.^{80 110} Some programs use 6-month intervals to suppress microfilarial counts to a level where transmission can be interrupted.⁸⁰

  
  


• 
  

  Adjunctive surgical excision of subcutaneous nodules may help eliminate microfilariae-producing adult worms,^{1 7 8} but there is no evidence that nodulectomies reduce blindness associated with onchocerciasis.⁸⁰

  
  

Strongyloidiasis

• 
  

  After treatment, perform follow-up stool examinations to verify eradication of S. stercoralis;¹ retreatment indicated if recrudescence of larvae observed.¹

  
  


• 
  

  Optimal dosage for treatment of intestinal strongyloidiasis in immunocompromised (e.g., HIV-infected) patients not established.¹ Several courses of therapy (i.e., at intervals of 2 weeks) may be necessary; cure may not be achieved.¹ Control of extra-intestinal strongyloidiasis in such patients is difficult; once-monthly suppressive treatment may be helpful.¹

  
  

Scabies†

• 
  

  Consider treating family members of patients with scabies since asymptomatic scabies is common.⁸⁰

  
  


• 
  

  Skin eruptions at scabies infestation sites may worsen (increased lesion count and inflammation) during the first few days after initiation of treatment.^{80 87}

  
  


• 
  

  Pruritus may persist 2–4 weeks after treatment while dead mites in the outer skin layers slough off with normal exfoliation.^{80 87}

  
  


• 
  

  HIV-infected patients with uncomplicated scabies should receive the same treatment as those without HIV infection.¹⁰

  
  


• 
  

  If used for treatment of Norwegian scabies†, multiple-dose regimen or use in conjunction with a topical scabicide is recommended to reduce risk of treatment failure.^{2 108 109} Immunocompromised patients, including those with HIV infection, are at increased risk of developing Norwegian scabies; such patients should be managed in consultation with an expert.¹⁰

  
  

Administration

Oral Administration

Administer orally.¹ Tablets should be taken on an empty stomach with water.¹

Dosage

Pediatric Patients

Safety and efficacy in children weighing <15 kg not established.¹

Ascariasis†

Ascaris lumbricoides infections†

Oral

150–200 mcg/kg as a single dose.³

Filariasis

Onchocerciasis (Filariasis Caused by Onchocerca volvulus)

Oral

Children weighing ≥15 kg: Approximately 150 mcg/kg as a single dose.¹

For individual patients, retreatment once every 6–12 months until asymptomatic;^{2 3} intervals as short as 3 months can be considered.¹

Approximate Single Dose for Treatment of Onchocerciasis (Based on Patient Weight) 1

Patient Weight (kg)	Single Oral Dose
15–25	3 mg
26–44	6 mg
45–64	9 mg
65–84	12 mg
≥85	150 mcg/kg

Alternatively, in some mass treatment and control programs, dosage is estimated based on height† since weighing recipients may be impractical (e.g., in rural areas of developing countries).^{80 86 88}

Approximate Single Dose for Treatment of Onchocerciasis in Mass Treatment Programs (Based on Patient Height†)8889

Patient Height (cm)	Single Oral Dose
90–119	3 mg
120–140	6 mg
141–158	9 mg
≥159	12 mg

Mansonella streptocerca Infections†

Oral

150 mcg/kg as a single dose.³

Wuchereria bancrofti Infections†

Oral

150–400 mcg/kg as a single dose has been used;^{63 64 65 66 76 77} often in conjunction with a single dose of albendazole or diethylcarbamazine.^{63 64 66 76 77}

Gnathostomiasis†

Gnathostoma spinigerum Infections†

Oral

200 mcg/kg once daily for 2 days.³

Hookworm Infections†

Cutaneous Larva Migrans (Creeping Eruption Caused by Dog and Cat Hookworms)†

Oral

200 mcg/kg once daily for 1–2 days.³

Strongyloidiasis

Treatment of Intestinal Strongyloides stercoralis Infections

Oral

Children weighing ≥15 kg: Approximately 200 mcg/kg as a single dose.¹ Alternatively, some clinicians recommend 200 mcg/kg once daily for 2 days.³

Manufacturer states that additional doses not generally necessary, but follow-up stool examinations necessary to verify eradication.¹ Retreat if recrudescence of larvae is observed.¹

Approximate Single Dose for Treatment of Intestinal Strongyloidiasis (Based on Patient Weight)1

Patient Weight (kg)	Single Oral Dose
15–24	3 mg
25–35	6 mg
36–50	9 mg
51–65	12 mg
66–79	15 mg
≥80	200 mcg/kg

Prevention of Strongyloides Hyperinfection in HSCT Candidates at Risk†

Oral

Children weighing ≥15 kg: 200 mcg/kg once daily for 2 days given prior to HSCT.⁹

In immunocompromised candidates, multiple courses at 2-week intervals may be required and cure may not be achievable.⁹

Trichuriasis†

Trichuris trichiura Infections†

Oral

200 mcg/kg once daily for 3 days.³

Pediculosis†

Pediculosis Capitis (Head Lice Infestation)†

Oral

200 mcg/kg once daily on days 1, 2, and 10.³

Alternatively, an initial 200-mcg/kg dose followed by an additional 200-mcg/kg dose given after 7–14 days.^{4 5 51 57 62}

Alternatively, an initial 300-mcg/kg dose followed by an additional 300-mcg/kg dose given after 7 days.⁸⁰

Pediculosis Pubis (Pubic Lice Infestation)†

Oral

200 mcg/kg as a single dose;³ an additional dose given after 10–14 days may be necessary in some patients.³

CDC recommends a 2-dose regimen using 250-mcg/kg doses given 2 weeks apart.¹⁰

Scabies†

Oral

200 mcg/kg as a single dose;^{3 46 68} an additional dose given after 10–14 days may be necessary in some patients.³

CDC recommends a 2-dose regimen using 200-mcg/kg doses given 2 weeks apart.¹⁰

Optimal number of doses has not been determined;¹⁰⁹ 2 doses usually recommended, especially in immunocompromised patients.^{3 4 5 10 32 46 47 51 52 60 108 109}

Crusted (Norwegian) Scabies†

Oral

Multiple-dose regimen consisting of 200-mcg/kg doses;^{10 52 108} some clinicians recommend doses be given once daily on days 1, 15, and 29.^{10 52}

Given with or without concomitant use of a topical scabicide (e.g., topical permethrin 5%).^{10 52 108}

Adults

Ascariasis†

Ascaris lumbricoides Infections†

Oral

150–200 mcg/kg as a single dose.³

Filariasis

Onchocerciasis (Filariasis Caused by Onchocerca volvulus)

Oral

Approximately 150 mcg/kg as a single dose.¹

For individual patients, retreatment once every 6–12 months until asymptomatic;^{2 3} intervals as short as 3 months can be considered.¹

Approximate Single Dose for Treatment of Onchocerciasis (Based on Patient Weight)1

Patient Weight (kg)	Single Oral Dose
15–25	3 mg
26–44	6 mg
45–64	9 mg
65–84	12 mg
≥85	150 mcg/kg

Alternatively, in some mass treatment and control programs, dosage is estimated based on height†; weighing recipients may be impractical (e.g., in rural areas of developing countries).^{80 86 88}

Approximate Single Dose for Treatment of Onchocerciasis in Mass Treatment Programs (Based on Patient Height†) 8889

Patient Height (cm)	Single Oral Dose
90–119	3 mg
120–140	6 mg
141–158	9 mg
≥159	12 mg

Mansonella Infections†

Oral

Filariasis caused by M. streptocerca†: 150 mcg/kg as a single dose.³

Filariasis caused by M. ozzardi†: 200 mcg/kg as a single dose has been used.³

Wuchereria bancrofti Infections†

Oral

150–400 mcg/kg as a single dose has been used;^{63 64 65 66 76 77} often in conjunction with a single dose of albendazole or diethylcarbamazine.^{63 64 66 76 77}

Gnathostomiasis†

Gnathostoma spinigerum Infections†

Oral

200 mcg/kg once daily for 2 days.³

Hookworm Infections†

Cutaneous Larva Migrans (Creeping Eruption Caused by Dog and Cat Hookworms)†

Oral

200 mcg/kg once daily for 1–2 days.³

Strongyloidiasis

Treatment of Intestinal Strongyloides stercoralis Infections

Oral

Approximately 200 mcg/kg as a single dose.¹ Alternatively, some clinicians recommend 200 mcg/kg once daily for 2 days.³

Manufacturer states that additional doses not generally necessary, but follow-up stool examinations necessary to verify eradication.¹ Retreat if recrudescence of larvae is observed.¹

Approximate Single Dose for Treatment of Intestinal Strongyloidiasis (Based on Patient Weight)1

Patient Weight (kg)	Single Oral Dose
15–24	3 mg
25–35	6 mg
36–50	9 mg
51–65	12 mg
66–79	15 mg
≥80	200 mcg/kg

Prevention of Strongyloides Hyperinfection in HSCT Candidates at Risk†

Oral

200 mcg/kg once daily given for 2 days prior to HSCT.⁹

In immunocompromised candidates, multiple courses at 2-week intervals may be required and cure may not be achievable.⁹

Trichuriasis†

Trichuris trichiura Infections†

Oral

200 mcg/kg once daily for 3 days.³

Pediculosis†

Pediculosis Capitis (Head Lice Infestation)†

Oral

200 mcg/kg once daily on days 1, 2, and 10.³

Alternatively, an initial 200-mcg/kg dose followed by an additional 200-mcg/kg dose given after 7–14 days.^{4 5 51 57 62}

Alternatively, an initial 300-mcg/kg dose followed by an additional 300-mcg/kg dose given after 7 days.⁸⁰

Pediculosis Pubis (Pubic Lice Infestation)†

Oral

200 mcg/kg as a single dose;³ an additional dose given after 10–14 days may be necessary in some patients.³

Alternatively, an initial 250-mcg/kg dose followed by an additional 250-mcg/kg dose after 7 days.⁸⁰

Scabies†

Oral

200 mcg/kg as a single dose.^{3 46 68}

Alternatively, 250–300 mcg/kg as a single dose.^{80 87}

A second dose may be required after 7–14 days, especially in immunocompromised patients.^{3 4 5 10 32 46 47 51 52 60}

Crusted (Norwegian) Scabies†

Oral

200 mcg/kg once daily on days 1, 15, and 29 recommended by CDC.¹⁰

Alternatively, 200 mcg/kg as a single dose in conjunction with a topical scabicide.^{10 52}

Cautions for Ivermectin

Contraindications

• 
  

  Hypersensitivity to ivermectin or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Mazzotti Reactions

Cutaneous and/or systemic reactions of varying severity (Mazzotti reactions) may occur in patients with onchocerciasis receiving microfilaricidal drugs (e.g., diethylcarbamazine, ivermectin).¹ These may be secondary to allergic and inflammatory responses to death of microfilariae.¹

Mazzotti reactions may include pruritus, edema, frank urticarial rash (papular and pustular), fever, arthralgia/synovitis, and lymph node enlargement/tenderness (e.g., axillary, cervical, inguinal).¹

Mazzotti-type reactions appear to be less severe and occur less frequently with ivermectin than with diethylcarbamazine.^{5 6 20 42}

These reactions may be most severe in previously untreated patients and may diminish with subsequent treatment (e.g., annual mass treatment and control programs).⁸⁰

Optimal treatment of severe Mazzotti reactions not determined.^{1 78} Oral or IV hydration, recumbency, and/or parenteral corticosteroids have been used to treat postural hypotension;¹ for supportive treatment of mild to moderate reactions, antihistamines, corticosteroids, and/or aspirin have been used.^{1 3}

Mazzotti-type reactions observed with treatment of onchocerciasis or the disease itself would not be anticipated in patients being treated for strongyloidiasis.¹

Ocular Effects

Ocular reactions (e.g., abnormal sensation in the eyes, eyelid edema, anterior uveitis, conjunctivitis, limbitis, keratitis, chorioretinitis or choroiditis) may occur in patients being treated for onchocerciasis or may occur secondary to the disease itself.¹

Ocular reactions observed with treatment of onchocerciasis or the disease itself would not be anticipated in patients being treated for strongyloidiasis.¹

Neurotoxicity

Not recommended in patients with an impaired blood-brain barrier (e.g., meningitis, African trypanosomiasis) or CNS disorders that may increase CNS penetration of the drug;^{2 4 13 91} potential interaction with CNS GABA receptors. (See Interactions.)^{2 4 13 91}

P-glycoprotein, encoded by the multi-drug resistance gene (MDR1), functions as a drug efflux transporter; appears to limit CNS uptake and prevent potentially fatal neurotoxicity.^{5 13 48 91 92}

Theoretical increased risk of neurotoxicity in patients with altered expression or function of p-glycoprotein (e.g. through genetic polymorphism, concomitant use of inhibitors of the p-glycoprotein transport system); if such increased susceptibility exists, apparently rare. (See Interactions.)^{5 48}

Although not reported in humans to date, neurotoxicity (e.g., tremors, ataxia, sweating, lethargy, coma, death) has occurred in certain animals with extreme sensitivity (e.g., collie dogs, inbred strains of mice);^{5 48 92} increased CNS sensitivity appears to be secondary to absent or dysfunctional MDR and p-glycoprotein.^{5 48 92}

General Precautions

Encephalopathy Risk in Onchocerciasis and Loiasis

Consider possible severe adverse effects when treating onchocerciasis in patients from areas where onchocerciasis and loiasis are co-endemic.^{3 16 54 78 79}

Patients with onchocerciasis who also are heavily infected with L. loa may develop serious or fatal neurologic events (e.g., encephalopathy, coma) either spontaneously or following rapid killing of microfilariae with effective microfilaricidal agents, including ivermectin.^{1 3 16 54 78 79}

Back pain, conjunctival hemorrhage, dyspnea, urinary and/or fecal incontinence, difficulty standing or walking, mental status changes, confusion, lethargy, stupor, seizures, coma, dysarthria or aphasia, fever, headache, or chills also reported.^{1 16 54 78}

Reported rarely in patients receiving ivermectin, but a definite causal relationship not established.^{1 54 93 94}

Pretreatment assessment for loiasis and careful post-treatment follow-up recommended when treatment is planned for any reason in patients with significant exposure to L. loa in endemic areas (West or Central Africa).^{1 16}

Other Precautions in Filariasis

Increased risk of severe adverse reactions (e.g., edema, aggravation of onchodermatitis) in patients with hyperreactive onchodermatitis (sowdah).¹

Does not kill adult O. volvulus worms, but decreases microfilarial load in skin for approximately 6–12 months following a single dose.^{1 2 8 11 18 20 80} Follow-up and retreatment required since the adult female worms continue to produce microfilaria for 9–15 years.^{5 7 19}

Specific Populations

Pregnancy

Category C.¹

Has been inadvertently given to pregnant women during mass distribution campaigns for treatment and control of onchocerciasis or lymphatic filariasis, but was not associated with adverse pregnancy outcomes, congenital malformations, or differences in developmental status or disease patterns in the offspring of such women.^{55 56 103 104}

WHO and other experts state that use for treatment of onchocerciasis after the first trimester probably is acceptable based on the high risk of infection-associated blindness if untreated.¹⁰⁴

Lactation

Distributed into milk.¹ Use in nursing women only when risk of delayed treatment in the woman outweighs risks to the nursing infant.^{1 104}

Pediatric Use

Safety and efficacy not established in children weighing <15 kg.¹

Some clinicians state that use not recommended in young children (e.g., those weighing <15 kg or <2 years of age) partly because the blood-brain barrier may be less developed than in older patients.^{5 95} (See Neurotoxicity under Cautions.)

Limited data suggest that safety in those 6–13 years of age similar to that in adults.¹

Geriatric Use

Insufficient experience in controlled clinical studies in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹ Other clinical experience has not revealed age-related differences in response.¹

Use with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.¹

Common Adverse Effects

Treatment of onchocerciasis: Worsening of Mazzotti reactions (see Mazzotti Reactions under Cautions),¹ ocular effects,¹ peripheral edema,¹ tachycardia,¹ eosinophilia.¹

Treatment of strongyloidiasis: GI effects (diarrhea,¹ nausea,¹ anorexia,¹ constipation,¹ vomiting,¹ abdominal pain,¹ abdominal distention),¹ decreased leukocyte count,¹ eosinophilia,¹ increased hemoglobin,¹ increased serum ALT or AST,¹ nervous system effects (dizziness,¹ asthenia or fatigue,¹ somnolence,¹ tremor,¹ vertigo),¹ pruritus,¹ rash,¹ urticaria.¹

Interactions for Ivermectin

Appears to be metabolized by CYP3A4.⁴¹

Drugs with GABA-potentiating Activity

Concomitant use with drugs with GABA-potentiating activity (e.g., barbiturates, benzodiazepines, sodium oxybate, valproic acid) not recommended.^{13 80} Ivermectin may interact with GABA receptors in the CNS.^{2 4 13 91}

Inducers or Inhibitors of the p-glycoprotein Transport System

Ivermectin appears to be a substrate of p-glycoprotein transport system.^{13 40 48 80} Theoretical possibility of interactions with inducers (e.g., amprenavir, clotrimazole, phenothiazines, rifampin, ritonavir, St. John’s wort) or inhibitors (e.g., amiodarone, carvedilol, clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole, quinidine, ritonavir, tamoxifen, verapamil) of this system.^{13 40 48 80} Concomitant use with inhibitors theoretically could result in increased brain concentrations of ivermectin and neurotoxicity^{5 48}

Specific Drugs

Drug	Interaction	Comments
Alcohol	Increased plasma ivermectin concentrations13 43	Clinical importance unknown13 43
Anticoagulants	Excessive hypocoagulability reported with acenocoumarol (not commercially available in the US) after occupational contact with insecticide formulations of ivermectin (Epimek, not commercially available in the US) and metidation (Ultracid, not commercially available in the US)13 74	Clinical importance unknown13
Benzodiazepines	Benzodiazepine effects may be potentiated13	Concomitant use not recommended13

Ivermectin Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations attained in about 4 hours.^{1 6 14 35}

Food

High-fat meal may increase absorption, but effect of food on bioavailability not evaluated using usual dosage (150–200 mcg/kg).^{1 33}

Distribution

Extent

Concentrated in liver and adipose tissue.⁴²

Does not readily cross blood-brain barrier.^{1 5 48 91} Brain uptake apparently limited by p-glycoprotein transport system.^{5 13 48 91 92} (See Neurotoxicity under Cautions.)

Distributed into milk in low concentrations.¹

Plasma Protein Binding

Approximately 93%;⁷⁵ principally albumin and, to a lesser extent, α ₁-acid glycoprotein.³⁴

Elimination

Metabolism

Metabolized in the liver,¹ principally by CYP3A4.⁴¹

Appears to be a substrate of the p-glycoprotein transport system.^{40 48 49}

El

Insulin Lispro Cartridges

Pronunciation: IN-su-lin LIS-pro
Generic Name: Insulin Lispro
Brand Name: Humalog

Insulin Lispro Cartridges are used for:

Treating diabetes mellitus. Insulin Lispro Cartridges are usually used with a longer-acting insulin or insulin pump therapy. In some patients, it may be used with a sulfonylurea antidiabetic instead of a longer-acting insulin.

Insulin Lispro Cartridges are a fast-acting form of the hormone insulin. It works by helping your body to use sugar properly. This lowers the amount of glucose in the blood, which helps to treat diabetes.

Do NOT use Insulin Lispro Cartridges if:

• you are allergic to any ingredient in Insulin Lispro Cartridges


• you are having an episode of low blood sugar

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

Before using Insulin Lispro Cartridges:

Some medical conditions may interact with Insulin Lispro Cartridges. 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 you drink alcoholic beverages or smoke


• if you have kidney or liver problems; nerve problems; adrenal, pituitary or thyroid problems; or diabetic ketoacidosis


• if you use 3 or more insulin injections per day


• if you are fasting, have high blood sodium levels, or are on a low salt diet

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

• Beta-blockers (eg, propranolol), clonidine, guanethidine, lithium, or reserpine because they may increase the risk of high or low blood sugar or may hide the signs and symptoms of low blood sugar, if it occurs


• Angiotensin-converting (ACE) inhibitors (eg, enalapril), disopyramide, fenfluramine, fibrates (eg, clofibrate, gemfibrozil), fluoxetine, monoamine oxidase inhibitors (MAOIs) (eg, phenelzine), oral medicine for diabetes (eg, glipizide, metformin, nateglinide), pentamidine, propoxyphene, salicylates (eg, aspirin), somatostatin analogs (eg, octreotide), or sulfonamide antibiotics (eg, sulfamethoxazole) because the risk of low blood sugar may be increased


• Corticosteroids (eg, prednisone), danazol, diuretics (eg, furosemide, hydrochlorothiazide), estrogen, hormonal contraceptives (eg, birth control pills), isoniazid, niacin, phenothiazines (eg, chlorpromazine), progesterones (eg, medroxyprogesterone), somatropin, sympathomimetics (eg, albuterol, epinephrine, terbutaline), or thyroid hormones (eg, levothyroxine) because they may decrease Insulin Lispro Cartridges's effectiveness, resulting in high blood sugar

This may not be a complete list of all interactions that may occur. Ask your health care provider if Insulin Lispro Cartridges 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 Insulin Lispro Cartridges:

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

• An extra patient leaflet is available with Insulin Lispro Cartridges. Talk to your pharmacist if you have questions about this information.


• Use Insulin Lispro Cartridges within 15 minutes before or immediately after a meal, unless directed otherwise by your doctor.


• If you will be using Insulin Lispro Cartridges at home, a health care provider will teach you how to use it. Be sure you understand how to use Insulin Lispro Cartridges. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• You may use Insulin Lispro Cartridges in an insulin pump if you are directed to do so by your doctor. If you are using an insulin pump, do NOT dilute Insulin Lispro Cartridges or mix it together with any other type of insulin.


• Insulin Lispro Cartridges should be clear and colorless. Do not use Insulin Lispro Cartridges if it contains particles, is cloudy or discolored, or if the vial or container is cracked or damaged.


• If you are mixing Insulin Lispro Cartridges with another insulin, draw Insulin Lispro Cartridges into the syringe first. Inject the dose immediately after mixing, as directed by your doctor.


• Use the proper technique taught to you by your doctor. Inject deep under the skin, NOT into a vein or muscle.


• Injection sites within an injection area (abdomen, thigh, upper arm) must be rotated from one injection to the next.


• Be sure you have purchased the correct insulin. Insulin comes in a variety of containers, including vials, cartridges, and pens. Make sure that you understand how to properly measure and prepare your dose. If you have any questions about measuring and preparing your dose, contact your doctor or pharmacist for information.


• Insulin Lispro Cartridges begins lowering blood sugar within minutes after an injection. The peak effect occurs within 30 to 90 minutes after a dose. The effect lasts for up to 2 to 5 hours.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• It is very important to follow your insulin regimen exactly. Do NOT miss any doses. Ask your doctor for specific instructions to follow in case you should ever miss a dose of insulin.

Ask your health care provider any questions you may have about how to use Insulin Lispro Cartridges.

Important safety information:

• Insulin Lispro Cartridges may cause dizziness, drowsiness, or changes in vision. These effects may be worse if you take it with alcohol or certain medicines. Use Insulin Lispro Cartridges with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not drink alcohol without discussing it with your doctor. Drinking alcohol may increase the risk of developing high or low blood sugar.


• Do not use more than the recommended dose, use Insulin Lispro Cartridges more often than prescribed, or change the type or dose of insulin you are using without checking with your doctor.


• Any change of insulin should be made cautiously and only under medical supervision. Changes in purity, strength, brand (manufacturer), type (regular, NPH, lente), species (beef, pork, beef-pork, human), and/or method of manufacture may require a change in dose.


• Illness, especially with nausea and vomiting, may cause your insulin requirements to change. Even if you are not eating, you will still require insulin. You and your doctor should establish a sick day plan to use in case of illness. When you are sick, test your blood/urine frequently and call your doctor as instructed.


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


• If you will be traveling across time zones, consult your doctor concerning adjustments in your insulin schedule.


• Carry an ID card at all times that says you have diabetes.


• An insulin reaction resulting from low blood sugar levels (hypoglycemia) may occur if you take too much insulin, skip a meal, or exercise too much. Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your heart beat faster; make your vision change; give you a headache, chills, or tremors; or make you more hungry. It is a good idea to carry a reliable source of glucose (eg, tablets or gel) to treat low blood sugar. If this is not available, you should eat or drink a quick source of sugar like table sugar, honey, candy, orange juice, or non-diet soda. This will raise your blood sugar level quickly. Tell your doctor right away if this happens. To prevent low blood sugar, eat meals at the same time each day and do not skip meals.


• Developing a fever or infection, eating significantly more than prescribed, or missing your dose of insulin may cause high blood sugar (hyperglycemia). High blood sugar may make you feel confused, drowsy, or thirsty. It can also make you flush, breathe faster, or have a fruit-like breath odor. If not treated, loss of consciousness, coma, or death may occur. If these symptoms occur, tell your doctor right away.


• Check with your doctor if you notice a depression in the skin or skin thickening at the injection site. You may need to change your injection technique.


• Proper diet, regular exercise, and regular testing of blood sugar are important for best results when using Insulin Lispro Cartridges.


• Lab tests, including fasting blood glucose levels and hemoglobin A_1c levels, may be performed while you use Insulin Lispro Cartridges. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Insulin Lispro Cartridges with caution in the ELDERLY; if low blood sugar occurs, it may be more difficult to recognize in these patients.


• Insulin Lispro Cartridges should be used with extreme caution in CHILDREN younger than 3 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Insulin Lispro Cartridges while you are pregnant. It is not known if Insulin Lispro Cartridges are found in breast milk. If you are or will be breast-feeding while you use Insulin Lispro Cartridges, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Insulin Lispro Cartridges:

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:

Redness, swelling, itching, or mild pain at the injection site.

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; wheezing; muscle pain); changes in vision; chills; confusion; dizziness; drowsiness; fainting; fast or irregular heartbeat; headache; loss of consciousness; mood changes; seizures; slurred speech; swelling; tremor; trouble breathing; trouble concentrating; unusual hunger; unusual sweating; weakness; wheezing.

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.

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 chills; dizziness; drowsiness; fainting; fast or irregular heartbeat; headache; loss of consciousness; nervousness; seizures; shakiness; sweating; tremor; vision changes; weakness.

Proper storage of Insulin Lispro Cartridges:

VIALS: Store new (unopened) vials in a refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze Insulin Lispro Cartridges. Store used (open) vials either in the refrigerator, between 36 and 46 degrees F (2 and 8 degrees C), or at room temperature, below 86 degrees F (30 degrees C). Store away from heat and light. If Insulin Lispro Cartridges has been frozen or overheated, throw it away. Throw away unrefrigerated or opened vials after 28 days, even if they still contain medicine.

CARTRIDGE SYSTEMS and PENS: Store new (unopened) cartridge systems or pens in a refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze Insulin Lispro Cartridges. Store used (open) cartridge systems or pens at room temperature, below 86 degrees F (30 degrees C). Do NOT store used (open) cartridges or pens in the refrigerator. Store away from heat and light. If Insulin Lispro Cartridges has been frozen or overheated, throw it away. Throw away unrefrigerated or used cartridge systems or pens after 28 days, even if they still contain medicine.

Avoid temperatures above 98.6 degrees F (37 degrees C). Do not leave Insulin Lispro Cartridges in a car on a warm or sunny day. Do not use Insulin Lispro Cartridges after the expiration date stamped on the label. Keep Insulin Lispro Cartridges, as well as syringes and needles, out of the reach of children and away from pets. If you are using Insulin Lispro Cartridges in an insulin pump, or if Insulin Lispro Cartridges has been mixed with other medicines or diluted, you may need to store it differently. Ask your doctor, pharmacist, or other health care provider how to store Insulin Lispro Cartridges.

General information:

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


• Insulin Lispro Cartridges are 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 Insulin Lispro Cartridges. 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 Insulin Lispro resources

• Insulin Lispro Use in Pregnancy & Breastfeeding
• Insulin Lispro Drug Interactions
• Insulin Lispro Support Group
• 4 Reviews for Insulin Lispro - Add your own review/rating

Compare Insulin Lispro with other medications

• Diabetes, Type 1
• Diabetes, Type 2

Introvale

Dosage Form: tablets
IntrovaleTM (levonorgestrel and ethinyl estradiol tablets, USP) 0.15 mg/0.03 mg

Rx only

Patients should be counseled that this product does not protect against HIV-infection (AIDS) and other sexually transmitted diseases.

Introvale Description

IntrovaleTM (levonorgestrel and ethinyl estradiol tablets, USP) is an extended-cycle oral contraceptive consisting of 84 peach active tablets each containing 0.15 mg of levonorgestrel, a synthetic progestogen and 0.03 mg of ethinyl estradiol, and 7 white inert tablets (without hormones).

The chemical formula of levonorgestrel USP is 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-, (-)-, and the chemical formula of ethinyl estradiol USP is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-. The structural formulas are as follows:

Each peach active tablet contains the following inactive ingredients: lactose anhydrous, magnesium stearate, povidone, polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, iron oxide yellow, iron oxide red and iron oxide black. Each white inert tablet contains the following inactive ingredients: lactose anhydrous, magnesium stearate, povidone, polyvinyl alcohol, polyethylene glycol, talc and titanium dioxide.

Introvale - Clinical Pharmacology

Mode of Action

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and changes in the endometrium (which reduce the likelihood of implantation).

Pharmacokinetics

Absorption

No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol tablets in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is approximately 43%.

Table 1: Mean ± SD Pharmacokinetic Parameters Following A Single Dose Administration of Two Tablets of Levonorgestrel and Ethinyl Estradiol Tablets in Healthy Female Subjects Under Fasting Conditions

 

Analyte	AUCt (mean ± SD)	Cmax (mean ± SD)	Tmax (mean ± SD)	T 1/2 (mean ± SD)
Levonorgestrel	60.8 ± 25.6 ng*hr/mL	5.6 ±1.5 ng/mL	1.4 ± 0.3 hours	29.8 ± 8.3 hours
Ethinyl estradiol	1307 ± 361 pg*hr/mL	145 ± 45 pg/mL	1.6 ± 0.5 hours	15.4 ± 3.2 hours

The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of levonorgestrel and ethinyl estradiol tablet has not been evaluated.

Distribution

The apparent volume of distribution of levonorgestrel and ethinyl estradiol are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol is about 95 to 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of combination levonorgestrel and ethinyl estradiol oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose kinetics, due in part, to increased SHBG levels that are induced by ethinyl estradiol, and a possible reduction in hepatic metabolic capacity.

Metabolism

Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.

First-pass metabolism of ethinyl estradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed ethinyl estradiol by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol hydroxylation. Hydroxylation at the 4-, 6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.

Excretion

About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of levonorgestrel and ethinyl estradiol tablet was about 30 hours.

Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinyl estradiol after a single dose of levonorgestrel and ethinyl estradiol tablet was found to be about 15 hours.

Special Populations

Race

No formal studies on the effect of race on the pharmacokinetics of levonorgestrel and ethinyl estradiol tablets were conducted.

Hepatic Insufficiency

No formal studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of levonorgestrel and ethinyl estradiol tablets. However, steroid hormones may be poorly metabolized in patients with impaired liver function.

Renal Insufficiency

No formal studies have been conducted to evaluate the effect of renal disease on the pharmacokinetics of levonorgestrel and ethinyl estradiol tablets.

Drug-Drug Interactions

See PRECAUTIONS section - Drug Interactions.

Indications and Usage for Introvale

IntrovaleTM are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

In a 1-year controlled clinical trial, 4 pregnancies occurred in women 18 to 35 years of age during 809 completed 91-day cycles of levonorgestrel and ethinyl estradiol tablets during which no backup contraception was utilized. This represents an overall use-efficacy (typical user efficacy) Pregnancy rate of 1.98 per 100 women-years of use.

Oral contraceptives are highly effective for pregnancy prevention. Table 2 lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and Norplant® Implant System, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE 2

Percentage of women experiencing an unintended pregnancy during the first year of typical use and the first year of perfect use of contraception and the percentage continuing use at the end of the first year: United States.

 

	% of Women Experiencing an Unintended Pregnancy within the First Year of Use		% of Women Continuing Use at One Year 3
Method (1)	Typical Use 1 (2)	Perfect Use 2 (3)	(4)
Chance 4	85	85
Spermicides 5	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation method		3
Sympto-thermal 6		2
Post-ovulation		1
Withdrawal	19	4
Cap 7
Parous women	40	26	42
Nulliparous women	20	9	56
Sponge
Parous women	40	20	42
Nulliparous women	20	9	56
Diaphragm 7	20	6	56
Condom 8
Female (Reality)	21	5	56
Male	14	3	61
Pill	5		71
Progestin only		0.5
Combined		0.1
IUD:
Progesterone T	2	1.5	81
Copper T 380A	0.8	0.6	78
LNg 20	0.1	0.1	81
Depo Provera	0.3	0.3	70
Norplant and Norplant-2	0.05	0.05	88
Female sterilization	0.5	0.5	100
Male sterilization	0.15	0.10	100
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. 9
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception. 10
Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998.
1 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an unintended pregnancy during the first year if they do not stop use for any other reason.
2 Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an unintended pregnancy during the first year if they do not stop use for any other reason.
3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
4 The percentages of women becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percentage who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
5 Foams, creams, gels, vaginal suppositories and vaginal film.
6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
7 With spermicidal cream or jelly.
8 Without spermicides.
9 The treatment schedule is one dose within 72 hours after unprotected intercourse and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 2 light-orange pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills).
10 However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced or the baby reaches six months of age.

Contraindications

Oral contraceptives should not be used in women who currently have the following conditions:

• Thrombophlebitis or thromboembolic disorders


• A past history of deep vein thrombophlebitis or thromboembolic disorders


• Cerebrovascular or coronary artery disease (current or history)


• Valvular heart disease with thrombogenic complications


• Uncontrolled hypertension


• Diabetes with vascular involvement


• Headaches with focal neurological symptoms


• Major surgery with prolonged immobilization


• Known or suspected carcinoma of the breast or personal history of breast cancer


• Carcinoma of the endometrium or other known or suspected estrogen-dependent
  
  neoplasia


• Undiagnosed abnormal genital bleeding


• Cholestatic jaundice of pregnancy or jaundice with prior pill use


• Hepatic adenomas or carcinomas, or active liver disease


• Known or suspected pregnancy


• Hypersensitivity to any component of this product

Warnings

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

The use of oral contraceptives is associated with increased risk of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension. The risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited thrombophilias, hypertension, hyperlipidemias, obesity and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower doses of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiological methods.

1. Thromboembolic Disorders and Other Vascular Problems

Use of levonorgestrel and ethinyl estradiol tablets provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing similar strength synthetic estrogens and progestins (an additional 9 weeks per year). While this added exposure may pose an additional risk of thrombotic and thromboembolic disease, studies to date with levonorgestrel and ethinyl estradiol tablets have not suggested an increased risk of these disorders.

a. Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30. Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Figure 1) among women who use oral contraceptives.

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). The severity and number of risk factors increase heart disease risk. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

b. Thromboembolism 

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The approximate incidence of deep vein thrombosis and pulmonary embolism in users of low dose (<50 mcg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5 to 3 per 10,000 woman-years for non-users. However, the incidence is less than that associated with pregnancy (6 per 10,000 woman-years). The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast-feed.

c. Cerebrovascular Diseases 

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity. Women with migraine (particularly migraine with aura) who take combination oral contraceptives may be at an increased risk of stroke.

d. Dose-Related Risk of Vascular Disease from Oral Contraceptives

A  positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient.

e.Persistence of Risk of Vascular Disease 

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40 to 49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.

2.Estimates of Mortality from Contraceptive Use

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 3). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is less than that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's--but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.

Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.

TABLE 3: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY-CONTROL METHOD AND ACCORDING TO AGE

 

Method of control and outcome	AGE
	15 to 19	20 to 24	25 to 29	30 to 34	35 to 39	40 to 44
No fertility - control methods*	7	7.4	9.1	14.8	25.7	28.2
Oral contraceptives non-smoker**	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives smoker**	2.2	3.4	6.6	13.5	51.1	117.2
IUD**	0.8	0.8	1	1	1.4	1.4
Condom*	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/ spermicide*	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence*	2.5	1.6	1.6	1.7	2.9	3.6

* Deaths are birth related

** Deaths are method related

Adapted from H.W. Ory, Family Planning Perspectives, 15: 57-63, 1983.

3. Carcinoma of the Reproductive Organs and Breasts

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives. Although the risk of having breast cancer diagnosed may be slightly increased among current and recent users of combined oral contraceptives (RR=1.24), this excess risk decreases over time after combination oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. The risk does not increase with duration of use and no consistent relationships have been found with dose or type of steroid. The patterns of risk are also similar regardless of a woman's reproductive history or her family breast cancer history. The subgroup for whom risk has been found to be significantly elevated is women who first used oral contraceptives before age 20, but because breast cancer is so rare at these young ages, the number of cases attributable to this early oral contraceptive use is extremely small. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in never-users. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone sensitive tumor.

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between oral contraceptive use and breast cancer and cervical cancers, a cause-and-effect relationship has not been established.

4. Hepatic Neoplasia

Benign hepatic adenomas are associated with oral contraceptive use, although their occurrence is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S., and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

5. Ocular Lesions

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

6. Oral Contraceptive Use Before or During Early Pregnancy

Because women using levonorgestrel and ethinyl estradiol tablets will likely have withdrawal bleeding only 4 times per year, pregnancy should be ruled out at the time of any missed menstrual period (see DOSAGE AND ADMINISTRATIONsection). Oral contraceptive use should be discontinued if pregnancy is confirmed.

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy (see CONTRAINDICATIONSsection).

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

7. Gallbladder Disease

Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.

8. Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.

A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a. and 1d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

9. Elevated Blood Pressure

Women with significant hypertension should not be started on hormonal contraceptive. An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens. Women with a history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see CONTRAINDICATIONSsection). For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.

10. Headache

The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (See WARNINGS, 1c.)

11. Bleeding Irregularities

When prescribing levonorgestrel and ethinyl estradiol tablets the convenience of fewer planned menses (4 per year instead of 13 per year) should be weighed against the inconvenience of increased intermenstrual bleeding and/or spotting.

The clinical trial (SEA 301) that compared the efficacy of levonorgestrel and ethinyl estradiol tablets (91-day cycles) to an equivalent dosage 28-day cycle regimen also assessed intermenstrual bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥10 consecutive days on oral contraceptives were excluded from the study. More levonorgestrel and ethinyl estradiol tablets subjects, compared to subjects on the 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [levonorgestrel and ethinyl estradiol tablets] vs. 1.8% [28-day cycle regimen]).

Table 4 shows the percentages of women with ≥7 days and ≥20 days of intermenstrual spotting and/or bleeding in the levonorgestrel and ethinyl estradiol tablets and the 28-day cycle treatment groups.

Table 4. Percentage of Subjects with Intermenstrual Bleeding and/or Spotting

 

Days of intermenstrual bleeding and/or spotting	Percentage of Subjects *
Levonorgestrel and Ethinyl Estradiol Tablets	Cycle 1 (N=385)	Cycle 4 (N=261)
≥7 days	65%	42%
≥20 days	35%	15%
28-day regimen	Cycles 1-4 (N=194)	Cycles 10-13 (N=158)
≥7 days	38%	39%
≥20 days	6%	4%

* Based on spotting and/or bleeding on days 1 to 84 of a 91 day cycle in the levonorgestrel and ethinyl estradiol tablets subjects and days 1 to 21 of a 28 day cycle over 4 cycles in the 28-day dosing regimen.

Total days of bleeding and/or spotting (withdrawal plus intermenstrual) were similar over one year of treatment for levonorgestrel and ethinyl estradiol tablets subjects and subjects on the 28-day cycle regimen.

As in any case of bleeding irregularities, n