Chemet

Generic Name: Succimer
Class: Heavy Metal Antagonists
ATC Class: V03AB
VA Class: AD300
Chemical Name: Meso 2,3-dimercaptosuccnic acid
Molecular Formula: C₄H₆O₄S₂
CAS Number: 304-55-2

Introduction

Heavy metal antagonist; chelates lead.^{1 2 3 4}

Uses for Chemet

Lead Poisoning

Alternative for treatment of lead poisoning in children with blood lead concentrations >45 mcg/dL^{1 2} (designated an orphan drug by FDA for this use).⁹

The AAP recommends succimer in the treatment of lead poisoning in children with blood lead concentrations of 45–70 mcg/dL who do not have symptoms of lead encephalopathy.⁵ Alternatively, parenteral therapy with edetate calcium disodium (calcium EDTA) alone is recommended.⁵

CDC and AAP do not recommend routine chelation therapy in pediatric patients with blood lead concentrations 25–45 mcg/dL.^{5 b} However, oral chelation therapy with succimer may be recommended in certain patients (e.g., blood lead concentrations of 35–44 mcg/dL, children <2 years of age, evidence of toxicity or symptoms).^{5 b}

The AAP currently states that patients with blood lead concentrations >70mcg/dL or with symptoms of lead encephalopathy require inpatient combined therapy with parenteral calcium EDTA and dimercaprol.^{4 5 8}

Children may need to be hospitalized during initiation of therapy to monitor for adverse effects, ensure patient compliance, and allow time for implementation of environmental lead abatement procedures.^{5 6}

Used in conjunction with a lead abatement program.^a

Notto be used prophylactically for the prevention of lead poisoning in a lead-containing environment.^{1 2}

Management of lead poisoning† in adults with blood lead concentrations 70–100 mcg/dL or mild symptoms.^b

Other Heavy Metal Poisoning

Has been used in the treatment of mercury poisoning† (designated an orphan drug by FDA for this use).^{1 2 9}

Has been used in the treatment of arsenic poisoning†.^{1 2 9}

Chemet Dosage and Administration

General

• 
  

  When source for lead poisoning has been identified, remove patient from that source.^a

  
  


• 
  

  Maintain adequate hydration to ensure renal excretion of chelating agents.^a

  
  

Administration

Oral Administration

Administer orally.^{1 2}

In patients who cannot swallow capsules, administer by opening capsule and sprinkling beads on a small amount of soft food or by putting beads in a spoon and following with fruit drink.^a

Dosage

Pediatric Patients

Lead Poisoning

Blood Lead Concentration 45–70 mcg/dL

Oral

Children >12 months of age: 10 mg/kg or 350 mg/m² every 8 hours for 5 days followed by 10 mg/kg or 350 mg/m² every 12 hours for 14 days.^{1 2 a b d} Full course of treatment is 19 days.^{1 2 a}

Intervals ≥2 weeks are recommended between courses of succimer therapy unless blood lead concentrations require more prompt drug therapy.^{1 2 a}

≥4 week interval is recommended when succimer is given subsequent to calcium EDTA therapy, with or without dimercaprol.^{1 2 a}

Adults

Lead Poisoning

Mild Symptoms or Blood Lead Concentration 70–100 mcg/dL

Oral

10 mg/kg or 350 mg/m² every 8 hours for 5 days followed by 10 mg/kg or 350 mg/m² every 12 hours for 14 days.^b Full course of treatment is 19 days.^b

Intervals ≥2 weeks are recommended between courses of succimer therapy unless blood lead concentrations require more prompt drug therapy.^{1 2}

≥4 week interval is recommended when succimer is given subsequent to calcium EDTA therapy, with or without dimercaprol.^{1 2}

Prescribing Limits

Pediatric Patients

Lead Poisoning

Oral

Children >12 months of age: Initially, maximum 10 mg/kg or 350 mg/m² every 8 hours.^{1 2}

Safety of uninterrupted dosing >3 weeks not established and not recommended.^a

Adults

Lead Poisoning

Oral

Safety of uninterrupted dosing >3 weeks not established and not recommended.^a

Special Populations

No special population dosage recommendations at this time.^a

Cautions for Chemet

Contraindications

• 
  

  Known hypersensitivity to succimer or any ingredient in the formulation.^a

  
  

Warnings/Precautions

Warnings

Lead Exposure

Not a substitute for the abatement of lead exposure.^a

Neutropenia

Risk of mild to moderate neutropenia, possibly resulting in infection.^a

Perform CBCs, including differential and platelet counts, prior to and weekly during therapy.^a Withhold therapy if ANC <1200/mm³; continue monitoring until ANC >1500/mm³ or recovery to patient’s baseline neutrophil count.^a Rechallenge only if the benefit of therapy outweighs the risk of neutropenia and only with careful monitoring.^a

Assess blood counts if infection is suspected.^a

Sensitivity Reactions

Hypersensitivity

Possible allergic or mucocutaneous reactions; may occur with readministration as well as during initial course.^a

Recurrent mucocutaneous vesicular eruptions affecting oral mucosa, external urethral meatus, and perianal area reported in one patient; reactions increased in severity with administration of each subsequent course and resolved between courses and upon discontinuance of therapy.^a

General Precautions

Monitoring

Clinical experience is limited; careful observation recommended during therapy.^a

Rebound Lead Toxicity

Risk of elevated blood lead concentrations and associated symptoms after discontinuance of drug due to redistribution of lead from bone stores to soft tissues and blood.^a

After completion of therapy, monitor blood lead concentrations at least once weekly until stable.^a Use the severity of lead intoxication (as measured by the initial blood lead concentration and the rate and degree of rebound of blood lead) as a guide for more frequent monitoring.^a

Elevated Serum Transaminases

Transient mild elevations of serum transaminases observed in 6–10% of patients.^a Obtain baseline and weekly serum transaminase levels during therapy.^a

Specific Populations

Pregnancy

Category C.^a

Lactation

Not known whether succimer is distributed into milk; however, breastfeeding is contraindicated in women receiving succimer due to maternal lead poisoning and risk of exposing nursing infant to the toxic heavy metal.^{a e}

Pediatric Use

Safety and efficacy not established in children <12 months of age.^a

Hepatic Impairment

Use with caution; assess hepatic function prior to and periodically during therapy.^a

Closely monitor patients with a history of liver disease.^a

Renal Impairment

Use with caution; assess renal function prior to and periodically during prolonged therapy.^a Adequately hydrate patients during therapy.^a Limited data suggests that succimer is dialyzable, but the lead chelates are not.^a

Common Adverse Effects

GI symptoms (nausea, vomiting, diarrhea, appetite loss, loose stools, metallic taste), elevated serum transaminases, rash, neutropenia.^a

Interactions for Chemet

Chelating Agents

Concomitant administration with other chelating agents (i.e., edetate sodium dicalcium) is not recommended.^c

Laboratory Tests

May interfere with serum and urinary laboratory tests.^a May cause false positive results for ketones in urine using nitroprusside reagents (e.g., Ketostix) and falsely decreased measurements of serum uric acid and CPK.^a

Chemet Pharmacokinetics

Absorption

Bioavailability

Absorption is rapid and variable, with peak plasma concentrations obtained at 1–2 hours.^a

Elimination

Metabolism

Approximately 90% of absorbed dose is metabolized to mixed succimer-cysteine disulfides.^a

Elimination Route

Unabsorbed drug excreted principally in feces; absorbed drug excreted principally in the urine as metabolites.^a

Half-life

Approximately 2 days.^a

Stability

Storage

Oral

Capsules

15–25°C.^a Avoid excessive heat.^a

ActionsActions

• 
  

  Chelates heavy metals with a high specificity for lead.^{4 a}

  
  


• 
  

  Forms water soluble chelates with lead and increases urinary excretion of lead.^a

  
  


• 
  

  At recommended oral doses, decreases average blood lead concentrations by 72.5%.^a An average of 19 mg of lead was excreted in urine following administration of 30 mg/kg of succimer daily for 5 days.^a

  
  


• 
  

  Improves clinical symptoms (e.g., headache, colic) and biochemical indices of lead poisoning.^a

  
  


• 
  

  Does not affect urinary elimination of iron, calcium, or magnesium; however, may double zinc excretion.^a

  
  

Advice to Patients

• 
  

  Importance of identifying source of lead poisoning and then removing patient from that source.^{1 2} Importance of patient residing in an environment free of lead both during and after therapy.^{1 2}

  
  


• 
  

  For patients unable to swallow capsules, contents of capsules may be sprinkled on soft food just before administration or placed on a spoon for administration and taken with fruit juice.^a

  
  


• 
  

  Importance of maintaining adequate fluid intake.^a

  
  


• 
  

  Importance of informing clinicians if rash or infection occurs.^a

  
  


• 
  

  Importance of completing full course of therapy.^a

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^a

  
  


• 
  

  Importance of keeping succimer out of reach of children.^a

  
  


• 
  

  Importance of informing patients of other important precautionary information.^a (See Cautions.)

  
  

Preparations

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

Succimer

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	100 mg	Chemet	Schwarz Pharma

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 August 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. McNeil Consumer Products Company. Chemet (succimer) capsules prescribing information. Fort Washington, PA; 1991 Feb.

2. McNeil Consumer Products Company. A summary of pharmacological and clinical data: Chemet (succimer). Fort Washington, PA: 1991.

3. McNeil, Fort Washington, PA: Personal communication.

4. US Department of Health and Human Services. Preventing lead poisoning in young children: a statement by the Centers for Disease Control October 1991. Atlanta, GA: Centers for Disease Control, Center for Environmental Health.

5. Committee on Drugs, American Academy of Pediatrics. Treatment guidelines for lead exposure in children. Pediatrics. 1995; 96:155-60. [IDIS 349805] [PubMed 7596706]

6. Committee on Environmental Health, American Academy of Pediatrics. Lead poisoning: from screening to primary prevention. Pediatrics. 1993; 92:176-83. [PubMed 8516071]

7. Mann KV, Travers JD. Succimer, an oral lead chelator. Clin Pharm. 1991; 10:914-22. [IDIS 288062] [PubMed 1663439]

8. Piomelli S, Rosen JF, Chisolm JJ Jr et al. Management of childhood lead poisoning. J Pediatr. 1984; 105:523-32. [IDIS 190925] [PubMed 6481529]

9. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

a. Schwarz Pharma Mfg. Chemet (succimer) capsules prescribing information. Seymour, IN; 2007 Apr.

b. Henretig FM. Lead. In: Flomenbaum NE, Goldfrank LR, Hoffman RS et al, eds. Goldfrank’s toxicologic emergencies. 8th ed. New York: McGraw-Hill; 2006:1308-24.

c. Howland MA. Succimer (2,3-dimercaptosuccinic acid). In: Flomenbaum NE, Goldfrank LR, Hoffman RS et al, eds. Goldfrank’s toxicologic emergencies. 8th ed. New York: McGraw-Hill; 2006:1325-30

d. Gracia RC, Snodgrass WR. Lead toxicity and chelation therapy. Am J Health-Syst Pharm. 2007; 64:45-53. [PubMed 17189579]

e. Briggs GC, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1706-8.

More Chemet resources

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

• Chemet Prescribing Information (FDA)


• Chemet MedFacts Consumer Leaflet (Wolters Kluwer)


• Chemet Concise Consumer Information (Cerner Multum)


• Chemet Advanced Consumer (Micromedex) - Includes Dosage Information


• Succimer Professional Patient Advice (Wolters Kluwer)

Compare Chemet with other medications

• Lead Poisoning, Severe

Skelid

Generic Name: tiludronate (Oral route)

tye-loo-DROE-nate

Commonly used brand name(s)

In the U.S.

• Skelid

Available Dosage Forms:

• Tablet

Therapeutic Class: Calcium Regulator

Chemical Class: Bisphosphonate

Uses For Skelid

Tiludronate is used to treat Paget's disease of the bone. This medicine is a bisphosphonate that helps make the bones stronger.

This medicine is available only with your doctor's prescription.

Before Using Skelid

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of tiludronate in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of tiludronate in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Anemia or


• Blood clotting problems or


• Cancer or use of cancer medicines or


• Dental or tooth problems or


• Infection or


• Poor oral hygiene—Use with caution. May increase risk for a serious side effect with the jaw.

• Barrett's esophagus or


• Bone or joint pain or


• Esophagus problems (e.g., difficulty with swallowing or inflammation) or


• Muscle pain, severe or


• Stomach or bowel problems (e.g., gastritis, heartburn or ulcers)—Use with caution. May make these conditions worse.

• Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Proper Use of Skelid

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance for unwanted effects.

Swallow the tablet whole with a large glass (8 ounces) of plain water. Do not drink mineral water, milk, coffee, juice, or any other liquid when you take the tablet. It is best to take this medicine on an empty stomach, either 2 hours before or 2 hours after eating.

Do not lie down for at least 30 minutes after taking this medicine.

It is important that you eat a well-balanced diet with an adequate amount of calcium and vitamin D while you are taking this medicine. Your doctor can help you choose the best diet for your condition.

If you use calcium supplements, mineral supplements, indomethacin, or aspirin, take them either 2 hours before or 2 hours after you take tiludronate. If you use antacids, wait at least 2 hours after your dose before you take the antacid. If you take these medicines together with tiludronate, it may keep the medicine from working properly.

Tiludronate takes up to 3 months to work. If you feel that the medicine is not working, talk to your doctor. Do not stop taking the medicine without checking with your doctor.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  
  • For treating Paget's disease:
    
    • Adults—400 milligrams (mg) once a day for at least 3 months.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Skelid

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. .

This medicine can irritate your esophagus. Stop taking this medicine and call your doctor right away if you have severe heartburn (new or worse than usual), pain with swallowing, chest pain, trouble with swallowing, or feel like food is getting stuck in your esophagus.

It is important that you tell all of your doctors or dentist that you are taking tiludronate. Make sure you tell your doctor about any new medical problems, especially with your teeth or jaw. If you have dental procedures while using this medicine, you may have an increased chance for serious jaw problems. Tell your doctor right away if you have any jaw tightness, swelling, numbness, or pain while using this medicine.

This medicine can cause muscle or joint pain that in some cases is very severe. Tell your doctor right away if you have bone, joint, or muscle pain while using this medicine.

Skelid Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Cough


• fever


• head congestion


• hoarseness or other voice changes


• nasal congestion


• runny nose


• sneezing


• sore throat

Less common

• Blindness


• blurred or decreased vision


• burning, dry, or itching eyes


• chest pain


• discharge or excessive tearing


• eye pain


• headache


• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid


• swelling of the face, feet, or lower legs


• unusual weight gain

Rare

• Bladder pain


• blistering, peeling, or loosening of the skin


• bloody or cloudy urine


• difficult, burning, or painful urination


• dizziness or lightheadedness


• fainting


• feeling of constant movement of self or surroundings


• frequent urge to urinate


• headache


• itching red skin lesions, often with a purple center


• lower back or side pain


• nervousness


• pain or swelling in the arms or legs without any injury


• pounding in the ears


• sensation of spinning


• slow or fast heartbeat


• sores, ulcers, or white spots in the mouth or on the lips

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Abdominal or stomach cramps


• confusion


• convulsions


• difficulty with breathing


• irregular heartbeats


• mood or mental changes


• muscle cramps in the hands, arms, feet, legs, or face


• numbness and tingling around the mouth, fingertips, or feet


• shortness of breath


• tremor

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Back pain


• body pain (general)


• diarrhea


• nausea


• upset stomach

Less common

• Bone fractures


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• confusion


• difficulty having a bowel movement (stool)


• dizziness


• dry skin


• hair loss


• increased thirst


• increased urination


• joint pain


• loss of appetite


• muscle cramps or spasms


• muscle pain


• red or irritated eyes


• skin rash


• stomach gas


• throat pain


• tooth disorder


• trouble thinking


• vomiting

Rare

• Dry mouth


• fear or nervousness


• feeling of warmth


• lack or loss of strength


• redness of the face, neck, arms and occasionally, upper chest


• sleepiness or unusual drowsiness


• stomach pain


• sleeplessness


• trouble sleeping


• unable to sleep


• unusual tiredness or weakness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Skelid side effects (in more detail)

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More Skelid resources

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

• Skelid Prescribing Information (FDA)


• Skelid Concise Consumer Information (Cerner Multum)


• Skelid MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Skelid with other medications

• Paget's Disease

anastrozole

an-AS-troe-zole

Commonly used brand name(s)

In the U.S.

• Arimidex

Available Dosage Forms:

• Tablet

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Aromatase Inhibitor

Uses For anastrozole

Anastrozole is used to treat certain types of breast cancer in women who have already stopped menstruating (postmenopausal). It is also used for women who have already had other cancer treatments (e.g., tamoxifen).

Many breast cancer tumors grow in response to estrogen. anastrozole interferes with the production of estrogen in the body. As a result, the amount of estrogen that the tumor is exposed to is reduced, limiting the growth of the tumor.

anastrozole is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, anastrozole is used in certain patients with the following medical conditions:

• Breast cancer, neoadjuvant treatment for hormone receptor-positive, operable or potentially operable, locally advanced disease in postmenopausal women (treatment for advanced breast cancer that may respond to surgery in women who have already stopped menstruating).

Before Using anastrozole

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For anastrozole, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to anastrozole or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of anastrozole in children.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of anastrozole in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	X	Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking anastrozole, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using anastrozole with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Tamoxifen

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of anastrozole. Make sure you tell your doctor if you have any other medical problems, especially:

• Bone problems (osteoporosis) or


• Hypercholesterolemia (high cholesterol or fat in the blood) or


• Ischemic heart disease (heart attack, angina), history of, or


• Liver disease—Use with caution. May make these conditions worse.

• Premenopausal women (have menstrual cycles)—Should not be used in these patients.

Proper Use of anastrozole

Take anastrozole only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance for side effects.

You may take anastrozole with or without food.

Anastrozole sometimes causes nausea, vomiting, or diarrhea. However, it is very important that you continue to use the medicine, even if you begin to feel ill. Ask your doctor for ways to prevent these effects or make them less severe.

anastrozole comes with a patient information leaflet. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Dosing

The dose of anastrozole will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of anastrozole. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  
  • For breast cancer:
    
    • Adults—1 milligram (mg) once a day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of anastrozole, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using anastrozole

It is important that your doctor check your progress at regular visits to make sure that anastrozole is working properly. Blood tests may be needed to check for unwanted effects.

It is unlikely that a postmenopausal woman may become pregnant. But, you should know that using anastrozole while you are pregnant could harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

anastrozole may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have itching; hives; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth while you are using anastrozole.

anastrozole may decrease bone mineral density when used for a long time. A low bone mineral density can cause weak bones or osteoporosis. If you have any questions about this, talk to your doctor.

anastrozole may increase your cholesterol or fat in the blood. If this happens, your doctor may give you medicine to lower the cholesterol and fat.

Stop taking anastrozole and check with your doctor right away if you start having chest pains or shortness of breath. anastrozole may increase the chance of heart attack or stroke in women who have a history of ischemic heart disease.

anastrozole Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Blurred vision


• chest pain or discomfort


• dizziness


• headache


• nervousness


• pounding in the ears


• shortness of breath


• slow or fast heartbeat


• swelling of the feet or lower legs

Less common

• Arm, back, or jaw pain


• chest tightness or heaviness


• cough or hoarseness


• difficult or painful urination


• dizziness, severe


• fever or chills


• headache, continuing


• increased blood pressure


• lower back or side pain


• nausea


• pain, tenderness, bluish color, or swelling of the foot or leg


• sore throat


• sudden shortness of breath


• sweating


• unusual tiredness or weakness


• vaginal bleeding (unexpected and heavy)

Incidence not known

• Blistering, peeling, or loosening of the skin


• hives


• itching, puffiness, or swelling of the eyelids or around the eyes, face, lips, or tongue


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• red skin lesions, often with a purple center


• sores, ulcers, or white spots in the mouth or on the lips


• welts

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Acid or sour stomach


• back pain


• belching


• body aches or pain


• bone pain


• congestion


• constipation


• decrease in height


• diarrhea


• dry mouth


• dryness or soreness of the throat


• feeling of warmth


• fever


• flushing or redness of the skin, especially on the face and neck


• heartburn


• hot flashes


• increased appetite


• indigestion


• lack or loss of strength


• loss of appetite


• mood or mental changes


• pain in the back, ribs, arms, or legs


• pain, general


• pelvic pain


• runny nose


• skin rash


• stomach discomfort, upset, or pain


• tender, swollen glands in the neck


• trouble in swallowing


• voice changes


• vomiting


• weakness


• weight loss

Less common

• Anxiety and confusion


• breast pain


• chills


• cough producing mucus


• difficulty breathing


• dryness of the vagina


• general feeling of discomfort or illness


• itching of the skin


• joint pain and stiffness


• loss of hair


• muscle pain


• numbness or tingling of the hands or feet


• shivering


• sleepiness or unusual drowsiness


• trouble sleeping or sleeplessness


• weight gain


• wheezing

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: anastrozole side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More anastrozole resources

• Anastrozole Side Effects (in more detail)
• Anastrozole Dosage
• Anastrozole Use in Pregnancy & Breastfeeding
• Drug Images
• Anastrozole Drug Interactions
• Anastrozole Support Group
• 17 Reviews for Anastrozole - Add your own review/rating

• Anastrozole Prescribing Information (FDA)


• Anastrozole Professional Patient Advice (Wolters Kluwer)


• Anastrozole Monograph (AHFS DI)


• Anastrozole MedFacts Consumer Leaflet (Wolters Kluwer)


• Arimidex Prescribing Information (FDA)


• Arimidex Consumer Overview

Compare anastrozole with other medications

• Breast Cancer
• Breast Cancer, Metastatic
• McCune-Albright Syndrome
• Pubertal Gynecomastia

clemastine

Generic Name: clemastine (CLEM as teen)

Brand names: Allerhist-1, Contac 12 Hour Allergy, Tavist, Tavist-1, Dailyhist-1, Tavist Allergy

What is clemastine?

Clemastine is an antihistamine. Clemastine blocks the effects of the naturally occurring chemical histamine in your body.

Clemastine is used to treat sneezing, runny nose, itching watery eyes, hives, rashes, itching, and other symptoms of allergies and the common cold.

Clemastine is may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about clemastine?

Use caution when driving, operating machinery, or performing other hazardous activities. Clemastine may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while you are taking clemastine.

Who should not take clemastine?

Do not take clemastine if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. A very dangerous drug interaction could occur, leading to serious side effects.

Before taking this medication, tell your doctor if you have

• 
  

  glaucoma or increased pressure in the eye;

  
  


• 
  

  a stomach ulcer;

  
  


• 
  

  an enlarged prostate, bladder problems, or difficulty urinating;

  
  


• 
  

  an overactive thyroid (hyperthyroidism);

  
  


• 
  

  hypertension or any type of heart problems; or

  
  


• 
  

  asthma.

  
  

You may not be able to take clemastine, or you may require a lower dose or special monitoring during treatment if you have any of the conditions listed above.

Clemastine is in the FDA pregnancy category B. This means that it is unlikely to harm an unborn baby. Do not take clemastine without first talking to your doctor if you are pregnant. Clemastine passes into breast milk. Infants are especially sensitive to the effects of antihistamines, and serious side effects could occur in a nursing baby. Clemastine is not recommended if you are breast-feeding a baby. Do not take clemastine without first talking to your doctor if you are nursing a baby. If you are over 60 years of age, you may be more likely to experience side effects from clemastine. You may require a lower dose of this medication.

How should I take clemastine?

Take clemastine exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water.

Clemastine can be taken with or without food.

To ensure that you get a correct dose, measure the syrup form of clemastine with a special dose-measuring spoon or cup, not with a regular tablespoon. If you do not have a dose-measuring device, ask your pharmacist where you can get one.

Never take more of this medication than is prescribed for you. The maximum amount of clemastine that you should take in 1 day is 8.04 mg.

Store clemastine at room temperature away from moisture and heat.

See also: Clemastine dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and take only your next regularly scheduled dose. Do not take a double dose of this medication unless otherwise directed by your doctor.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of a clemastine overdose include extreme sleepiness, confusion, weakness, ringing in the ears, blurred vision, large pupils, dry mouth, flushing, fever, shaking, insomnia, hallucinations, and possibly seizures.

What should I avoid while taking clemastine?

Use caution when driving, operating machinery, or performing other hazardous activities. Clemastine may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. Use alcohol cautiously. Alcohol may increase drowsiness and dizziness while you are taking clemastine.

Clemastine side effects

Stop taking clemastine and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives).

Other, less serious side effects may be more likely to occur. Continue to take clemastine and talk to your doctor if you experience

• 
  

  sleepiness, fatigue, or dizziness;

  
  


• 
  

  headache;

  
  


• 
  

  dry mouth; or

  
  


• 
  

  difficulty urinating or an enlarged prostate.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

Clemastine Dosing Information

Usual Adult Dose for Allergic Rhinitis:

Initial dose: 1.34 mg orally twice a day. Dosage may be increased as required, but not to exceed 2.68 mg orally 3 times a day.

Usual Adult Dose for Urticaria:

Initial dose: 1.34 mg orally twice a day. Dosage may be increased as required, but not to exceed 2.68 mg orally 3 times a day.

Usual Adult Dose for Allergic Reaction:

Initial dose: 1.34 mg orally twice a day. Dosage may be increased as required, but not to exceed 2.68 mg orally 3 times a day

Usual Pediatric Dose for Allergic Reaction:

0.335 to 0.67 mg/day orally divided into 2 or 3 doses. Maximum daily dose is 1.34 mg.

6 to 12 years:

0.67 to 1.34 mg orally twice a day. Maximum daily dose is 4.02 mg.

> 12 years:

Initial dose: 1.34 mg orally twice a day. Dosage may be increased as required, but not to exceed 2.68 mg orally 3 times a day.

Usual Pediatric Dose for Allergic Rhinitis:

0.335 to 0.67 mg/day orally divided into 2 or 3 doses. Maximum daily dose is 1.34 mg.

6 to 12 years:

0.67 to 1.34 mg orally twice a day. Maximum daily dose is 4.02 mg.

> 12 years:

Initial dose: 1.34 mg orally twice a day. Dosage may be increased as required, but not to exceed 2.68 mg orally 3 times a day.

Usual Pediatric Dose for Urticaria:

0.335 to 0.67 mg/day orally divided into 2 or 3 doses. Maximum daily dose is 1.34 mg.

6 to 12 years:

0.67 to 1.34 mg orally twice a day. Maximum daily dose is 4.02 mg.

> 12 years:

Initial dose: 1.34 mg orally twice a day. Dosage may be increased as required, but not to exceed 2.68 mg orally 3 times a day.

What other drugs will affect clemastine?

Do not take clemastine if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) in the last 14 days. A very dangerous drug interaction could occur, leading to serious side effects.

Talk to your pharmacist before taking other over-the-counter cough, cold, allergy, or insomnia medications. These may contain medicines similar to clemastine, which could lead to an overdose of antihistamine.

Before taking this medication, tell your doctor if you are taking any of the following medicines:

• 
  

  anxiety or sleep medicines such as alprazolam (Xanax), diazepam (Valium), chlordiazepoxide (Librium), temazepam (Restoril), or triazolam (Halcion);

  
  


• 
  

  medications for depression such as amitriptyline (Elavil), doxepin (Sinequan), nortriptyline (Pamelor), fluoxetine (Prozac), sertraline (Zoloft), or paroxetine (Paxil); or

  
  


• 
  

  any other medications that make you feel drowsy, sleepy, or relaxed.

  
  

Drugs other than those listed here may also interact with clemastine. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

More clemastine resources

• Clemastine Side Effects (in more detail)
• Clemastine Dosage
• Clemastine Use in Pregnancy & Breastfeeding
• Drug Images
• Clemastine Drug Interactions
• Clemastine Support Group
• 1 Review for Clemastine - Add your own review/rating

• Clemastine Prescribing Information (FDA)


• Clemastine MedFacts Consumer Leaflet (Wolters Kluwer)


• Clemastine Fumarate Monograph (AHFS DI)


• Tavist Consumer Overview

Compare clemastine with other medications

• Allergic Reactions
• Hay Fever
• Urticaria

Where can I get more information?

• Your pharmacist has more information about clemastine written for health professionals that you may read.

See also: clemastine side effects (in more detail)

Nizoral Tablets

1. Name Of The Medicinal Product

Nizoral 200 mg Tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 200 mg ketoconazole.

Excipient: Each tablet contains 19 mg lactose.

For a full list of excipients, see 6.1.

3. Pharmaceutical Form

Tablet.

White, circular, flat bevelled-edge, half scored tablet marked 'JANSSEN' on one side and 'K/200' on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Because of the risk for serious hepatic toxicity, Nizoral 200 mg tablets should be used only when the potential benefits are considered to outweigh the potential risks, taking into consideration the availability of other effective antifungal therapy.

Indications are:

Treatment of dermatophytosis and Malassezia (previously called Pityrosporum) folliculitis that cannot be treated topically because of the site, extent of the lesion or deep infection of the skin, in patients resistant to, or intolerant of, fluconazole, terbinafine and itraconazole.

Treatment of chronic mucocutaneous candidosis, cutaneous candidosis, and oropharyngeal candidosis that cannot be treated topically because of the site, extent of the lesion or deep infection of the skin, in patients resistant to or intolerant of both fluconazole and itraconazole.

4.2 Posology And Method Of Administration

Method of administration:

Oral.

Nizoral 200 mg tablets should be taken during meals for maximal absorption.

Dosage:

Adults

One tablet (= 200 mg) once daily with a meal. If no adequate response is obtained with this dose, the dose should be increased to 2 tablets (= 400 mg) once daily.

Children

- Children weighing from 15 to 30 kg: half a tablet (=100 mg) once daily with a meal.

- Children weighing more than 30 kg: same as for adults.

Duration of Treatment

For all indications, treatment should be continued without interruption until clinical parameters or laboratory tests indicate that the fungal infection has resolved. An inadequate treatment period may lead to recurrence of the active infection. However, the risk of serious hepatic toxicity increases with longer duration of treatment; courses of greater than 10 days should only be given after full consideration of the extent of treatment response and the risk benefit of continuing treatment, and liver function should be closely monitored (see section 4.4 Special warnings and precautions for use)

For the treatment of Malassezia infections, treatment should not normally exceed 4 weeks.

Special Patient Population: Hepatic Impairment (see 4.3 Contraindications)

4.3 Contraindications

Nizoral 200 mg tablets are contraindicated in the following situations:

- in patients with a known hypersensitivity to ketoconazole, to any of the other excipients, or to any other imidazole antifungal.

- In patients with acute or chronic liver disease.

- Co-administration of the CYP3A4 substrates astemizole, bepridil, halofantrine, disopyramide, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole or terfenadine with Nizoral 200 mg tablets is contraindicated since increased plasma concentrations of these medicinal products can lead to QT prolongation and rare occurrences of torsades de pointes.

- Co-administration of triazolam and oral midazolam.

- Co-administration of CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin.

- Co-administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).

- Co-administration of nisoldipine

- Co-administration of eplerenone

- Co-administration of irinotecan

- Co-administration of everolimus and sirolimus (= rapamycin)

See also 4.5 Interaction with other medicinal products and other forms of interaction.

4.4 Special Warnings And Precautions For Use

Because of the risk for serious hepatic toxicity, Nizoral 200 mg tablets should be used only when the potential benefits are considered to outweigh the potential risks, taking into consideration the availability of other effective antifungal therapy.

Hepatic toxicity

Very rare cases of serious hepatic toxicity, including cases with a fatal outcome or requiring liver transplantation, have occurred with the use of oral ketoconazole (see 4.8 Undesirable effects). Some patients had no obvious risk factors for liver disease. Cases have been reported that occurred within the first month of treatment, including some within the first week.

The risk of serious hepatic toxicity increases with longer duration of treatment; courses of greater than 10 days should only be given after full consideration of the extent of treatment response and the risk benefit of continuing treatment

All patients should be counselled at the start of treatment with basic knowledge of the signs and symptoms suggestive of liver toxicity. The patient should be informed to discontinue treatment if they feel unwell or in the event of symptoms such as anorexia, nausea, vomiting, fatigue, jaundice, abdominal pain or dark urine. If these occur, treatment should be stopped immediately and liver function testing should be conducted.

Monitoring of hepatic function

Liver function must be monitored in all patients receiving treatment with Nizoral 200 mg tablets.

Monitor liver function prior to treatment to rule out acute or chronic liver disease (see 4.3 Contraindications).

Liver function must be monitored at weeks 2 and 4 of treatment, then continued monthly, with discontinuation of treatment if any liver parameters are elevated above 3 times the normal limit.

In patients with raised liver enzymes, or those who have experienced liver toxicity with other drugs, treatment should only be started in exceptional cases, where the expected benefit exceeds the risk of hepatic injury, and consideration should be given to monitoring liver function tests (LFTs) more frequently.

Decreased gastric acidity

Absorption is impaired when gastric acidity is decreased. Acid neutralising medicines (e.g. aluminium hydroxide), should not be administered for at least 2 hours after the intake of Nizoral 200 mg tablets. In patients with achlorhydria, such as certain AIDS patients and patients on acid secretion suppressors (e.g. H₂-antagonists, proton pump inhibitors), it is advisable to administer Nizoral 200 mg tablets with a cola beverage.

Monitoring of adrenal function

In volunteers on daily doses of 400 mg and more, ketoconazole has been shown to reduce the cortisol response to ACTH stimulation. Therefore, adrenal function should be monitored in patients with Addison's Disease, adrenal insufficiency or borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.), and in patients on prolonged therapy presenting signs and symptoms suggestive of adrenal insufficiency.

Documented use of Nizoral 200 mg tablets in children weighing less than 15 kg is very limited. Therefore it is not recommended to administer Nizoral 200 mg tablets to small children.

A risk/benefit evaluation should be made before ketoconazole is used in cases of non-life threatening diseases requiring long treatment periods.

Drug interaction potential

Nizoral 200 mg has a potential for clinically important drug interactions (see 4.5 Interaction with other medicinal products and other forms of interaction).

Use with domperidone

A slight increase of QT interval (mean less than 10msec) was reported in a drug-drug interaction study with oral domperidone. Even if the significance of this study is not fully clear, alternative therapeutic options should be considered if oral ketoconazole treatment is required (see also sections 4.5).

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

1. Drugs affecting the absorption of ketoconazole

Drugs affecting gastric acidity impair the absorption of ketoconazole: see 4.4 Special warnings and precautions for use.

2. Drugs affecting the metabolism of ketoconazole

Ketoconazole is mainly metabolised through the cytochrome CYP3A4.

Enzyme-inducing drugs such as rifampicin, rifabutin, carbamazepine, isoniazid, nevirapine and phenytoin significantly reduce the bioavailability of ketoconazole. As plasma levels are lower than those expected if ketoconazole is used alone (no co-medication), it is not really necessary to monitor plasma levels. The combination of ketoconazole with potent enzyme inducers is not recommended.

Ritonavir increases the bioavailability of ketoconazole. Therefore, when it is given concomitantly, a dose reduction of ketoconazole should be considered.

3. Effect of ketoconazole on the metabolism of other drugs

Ketoconazole can inhibit the metabolism of drugs metabolised by certain hepatic P450 enzymes, especially of the CYP3A family. This can result in an increase and/or prolongation of their effects including adverse effects.

Co-administration of ketoconazole and domperidone is not recommended since the combination can lead to increased plasma concentrations of domperidone and QT prolongation.

Drugs that are contraindicated during treatment with ketoconazole (see 4.3 Contraindications):

Co-administration of the CYP3A4 substrates astemizole, bepridil, halofantrine, disopyramide, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole or terfenadine with Nizoral 200 mg tablets is contraindicated since increased plasma concentrations of these medicinal products can lead to QT prolongation and rare occurrences of torsades de pointes.

Co-administration of triazolam and oral midazolam is contraindicated because of an exaggerated and prolonged pharmacodynamic response.

Co-administration of CYP3A4 metabolised HMG-CoA reductase inhibitors such as simvastatin and lovastatin.

Co-administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine))

Co-administration of nisoldipine.

Co-administration of eplerenone.

Co-administration of irinotecan

Co-administration of everolimus and sirolimus (= rapamycin)

When co-administered with oral ketoconazole the following drugs should be used with caution and their plasma concentrations, effects or adverse effects should be monitored. Their dosage, if coadministered with ketoconazole, should be reduced if necessary. This should be considered when prescribing concomitant medication.

Examples include:

• Oral anticoagulants.

• HIV Protease Inhibitors such as indinavir, saquinavir.

• Certain antineoplastic agents such as vinca alkaloids, busulphan, docetaxel, erlotinib and imatinib;

• CYP3A4 metabolised calcium channel blockers such as the dihydropyridines and probably verapamil.

• Certain immunosuppressive agents: ciclosporin and tacrolimus

• Certain CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin

• Certain glucocorticoids such as budesonide, fluticasone, dexamethasone and methylprednisolone

• Digoxin (via inhibition of P-glycoprotein)

• Others: cilostazol, buspirone, alfentanil, fentanyl, sildenafil, solifenacin, alprazolam, brotizolam, intravenous midazolam, quetiapine, , repaglinide, tolterodine, trimetrexate, ebastine, eletriptan and reboxetine

Exceptional cases of a disulfiram-like reaction to alcohol, characterised by flushing, rash, peripheral oedema, nausea and headache, have been reported. All symptoms resolved completely within a few hours.

4.6 Pregnancy And Lactation

Pregnancy

There is limited information on the use of Nizoral 200 mg tablets during pregnancy. Animal studies have shown reproductive toxicity (see 5.3 Preclinical safety data). The potential risk to humans is unknown. Therefore, Nizoral 200 mg tablets should not be used during pregnancy unless the potential benefit to the mother outweighs the possible risk to the foetus.

Lactation

Since ketoconazole is excreted in the milk, mothers who are under treatment should not breast-feed whilst being treated with Nizoral 200 mg tablets.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

Clinical trials

In a multinational multi-centre, open label study in patients with various superficial and deep mycoses, adverse events during ketoconazole treatment were evaluable in 1361 cases, 149 (11%) reported adverse events. The adverse events were summarised regardless of the causality assessment of the investigator. The most frequently reported adverse events were of gastrointestinal origin, i.e. nausea and vomiting. Adverse events that were reported with an incidence of

Table 1: Adverse Experiences With an Incidence
System Organ Class AE Preferred term	Superficial Mycosis	Deep Mycosis	Total
% (N=1,026)	% (N=335)	% (N=1361)
Nervous system disorder
Headache	0.7	0.9	0.7
Dizziness	0.5	1.2	0.7
Somnolence	0.5	1.2	0.7
Gastrointestinal disorders
Nausea/Vomiting	1.8	6.9	3.0
Abdominal pain	1.2	1.2	1.2
Diarrhoea	0.7	0.6	0.7
Skin and subcutaneous tissue disorders
Pruritus	0.8	3.3	1.4
Rash	0.6	0.6	0.6

Postmarketing Experience

Including the above mentioned Adverse Drug Reactions (ADRs), the following ADR's have been observed from post-markleting experiences reported with the use of Nizoral 200 mg tablets. Unlike for clinical trials, precise frequencies cannot be provided for spontaneous reports. The frequency for these reports is therefore classified as 'not known'.

Table 2. Postmarketing reports of adverse drug reactions
Blood and the lymphatic system disorders
Not Known	thrombocytopenia;
Immune system disorders
Not Known	allergic conditions including anaphylactic shock anaphylactoid and anaphylactic reactions and angioneurotic oedema
Endocrine disorders
Not Known	adrenocortical insufficiency
Nervous system disorders
Not Known	Reversible increased intracranial pressure (e.g. papilloedema, fontanelle bulging in infants), paraesthesia
Eye disorders
Not Known	photophobia
Gastrointestinal disorders
Not Known	dyspepsia,
Hepato-biliary disorders
Not Known	serious hepatotoxicity, including jaundice, hepatitis, biopsy-confirmed hepatic necrosis, cirrhosis, hepatic failure including cases resulting in transplantation or death. (see 4.4 Special warnings and special precautions for use), liver function test abnormal
Skin and subcutaneous tissue disorders
Not Known	urticaria, alopecia, photosensitivity
Reproductive system and breast disorders
Not Known	erectile dysfunction, gynaecomastia, menstrual disorder; with doses higher than the recommended therapeutic dose of 200 or 400mg daily azoospermia

4.9 Overdose

There is no known antidote to ketoconazole.

In the event of accidental overdose, treatment consists of supportive measures. Within the first hour after ingestion gastric lavage may be performed. Activated charcoal may be given if considered appropriate.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic classification: Antimycotics for systemic use, imidazole derivatives

ATC code: J02A B02

Ketoconazole is an imidazole-dioxolane anti-mycotic, which is effective after oral administration and has a broad spectrum of activity against dermatophytes, yeasts and other pathogenic fungi.

In vitro studies have demonstrated that ketoconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.

Data from some clinical PK/PD studies and drug interaction studies suggest that oral dosing with ketoconazole at 200 mg twice daily for 3-7 days can result in a small increase of the QTc interval: a mean maximum increase of about 6 to 12 msec was seen at ketoconazole peak plasma levels, about 1-4 hours after ketoconazole administration. This small prolongation of the QTc interval, however, is not considered to be clinically relevant.

At the therapeutic dosage of 200 mg once daily, a transient decrease in the plasma concentrations of testosterone can be observed. Testosterone concentrations return to pre-dose concentrations within 24 hours after administration of ketoconazole has stopped. During long-term therapy at this dosage, testosterone concentrations are usually not significantly different from controls.

In volunteers on daily doses of 400 mg and more, ketoconazole has been shown to reduce the cortisol response to ACTH stimulation (see 4.4 Special warnings and precautions for use).

5.2 Pharmacokinetic Properties

Absorption

Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption. Mean peak plasma concentrations of approximately 3.5 µg/ml are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal.

Distribution

In vitro, the plasma protein binding is about 99% mainly to the albumin fraction. Ketoconazole is widely distributed into tissues; however, only a negligible proportion of ketoconazole reaches the cerebral-spinal fluid.

Metabolism

Following absorption from the gastro-intestinal tract, ketoconazole is converted into several inactive metabolites. The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation.

Excretion

Plasma elimination is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. About 13% of the dose is excreted in the urine, of which 2 to 4% is unchanged drug. The major route of excretion is through the bile into the intestinal tract.

Conditions in special populations

In patients with hepatic or renal insufficiency the overall pharmacokinetics of ketoconazole were not significantly different when compared with healthy subjects. See 4.3 Contraindications and 4.4 Special warnings and precautions for use.

5.3 Preclinical Safety Data

Slight pathological changes in the kidney, adrenals and ovaries were noted in an 18-month repeated dose rat study. In addition, female rats showed an increase in bone fragility. The No Observed Adverse Effect Level (NOAEL) in both these studies was 10 mg/kg/day.

In reproduction studies, at very high, maternally toxic doses (80 mg/kg/day and higher), ketoconazole impaired female fertility in the rat, and produced embryotoxic and teratogenic (oligodactylia and syndactylia) effects in pups. At 40 mg/kg in rats and rabbits, ketoconazole was devoid of embryotoxicity, teratogenicity and effects on fertility. No teratogenic effects were observed in mice at any dose level tested up to a maximum of 160 mg/kg. In pre-clinical studies, ketoconazole was not carcinogenic or genotoxic.

Electrophysiological studies have shown that ketoconazole inhibits the rapidly activating component of the cardiac delayed rectifier potassium current, prolongs the action potential duration, and may prolong the QT interval.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize starch

Lactose

Polyvidone K90

Microcrystalline cellulose

Colloidal anhydrous silica

Magnesium stearate

6.2 Incompatibilities

Not Applicable

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 30°C.

Store in the original package to protect from moisture.

6.5 Nature And Contents Of Container

PVC/aluminium blister packs containing 30 tablets

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Bucks

HP12 4EG

UK

8. Marketing Authorisation Number(S)

PL 00242/0083

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of First Authorisation: 22 December 1980

Date of renewal: 25 March 2003

10. Date Of Revision Of The Text

25 June 2010