Lexxel

Generic Name: enalapril and felodipine (Oral route)

en-AL-a-pril MAL-ee-ate, fe-LOE-di-peen

Oral routeTablet, Extended Release

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, enalapril maleate/felodipine should be discontinued as soon as possible .

ACE inhibitors can cause injury or death to the developing fetus when used during the second and third trimesters. Stop therapy as soon as possible when pregnancy is detected .

Commonly used brand name(s):

In the U.S.

• Lexxel

Available Dosage Forms:

• Tablet, Extended Release

Therapeutic Class: ACE Inhibitor/Calcium Channel Blocker Combination

Pharmacologic Class: Enalapril

Chemical Class: Dihydropyridine

Uses For Lexxel

Enalapril and felodipine combination belongs to the class of medicines called high blood pressure medicines (antihypertensives). This medicine is used to treat high blood pressure (hypertension).

High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if blood pressure is controlled.

The exact way in which this medicine works is not known. Enalapril is a type of medicine known as an angiotensin-converting enzyme (ACE) inhibitor. It blocks an enzyme in the body that is necessary in producing a substance that causes blood vessels to tighten. Felodipine is a type of medicine known as a calcium channel blocker. Calcium channel blocking agents affect the movement of calcium into the cells of the heart and blood vessels. The actions of both medicines relax blood vessels, lower blood pressure, and increase the supply of blood and oxygen to the heart.

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

Enalapril and felodipine combination was discontinued by the manufacturer on July 2, 2008.

Before Using Lexxel

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

Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of enalapril and felodipine in children with use in other age groups.

Geriatric

Although this medicine has not been shown to cause different side effects or problems in older people than it does in younger adults, blood levels of the felodipine component may be increased in the elderly.

Pregnancy

	Pregnancy Category	Explanation
1st Trimester	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.
2nd Trimester	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.
3rd Trimester	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

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

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Allopurinol


• Amiloride


• Amiodarone


• Atazanavir


• Azathioprine


• Canrenoate


• Cyclosporine


• Dantrolene


• Droperidol


• Eplerenone


• Fentanyl


• Interferon Alfa-2a


• Mibefradil


• Potassium


• Spironolactone


• Triamterene

Using this medicine 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.

• Acebutolol


• Aceclofenac


• Acemetacin


• Alclofenac


• Aliskiren


• Alprenolol


• Amprenavir


• Apazone


• Aspirin


• Atenolol


• Azosemide


• Bemetizide


• Bendroflumethiazide


• Benoxaprofen


• Benzthiazide


• Betaxolol


• Bevantolol


• Bisoprolol


• Bromfenac


• Bucindolol


• Bufexamac


• Bumetanide


• Bupivacaine


• Buthiazide


• Capsaicin


• Carprofen


• Carteolol


• Carvedilol


• Celecoxib


• Celiprolol


• Chlorothiazide


• Chlorthalidone


• Clometacin


• Clomipramine


• Clonixin


• Clopamide


• Cyclopenthiazide


• Cyclothiazide


• Dalfopristin


• Dexketoprofen


• Diclofenac


• Diflunisal


• Dilevalol


• Dipyrone


• Droxicam


• Esmolol


• Ethacrynic Acid


• Etodolac


• Etofenamate


• Felbinac


• Fenbufen


• Fenoprofen


• Fentiazac


• Floctafenine


• Fluconazole


• Flufenamic Acid


• Flurbiprofen


• Furosemide


• Gold Sodium Thiomalate


• Hydrochlorothiazide


• Hydroflumethiazide


• Ibuprofen


• Indapamide


• Indinavir


• Indomethacin


• Indoprofen


• Isoxicam


• Itraconazole


• Ketoconazole


• Ketoprofen


• Ketorolac


• Labetalol


• Levobunolol


• Lornoxicam


• Magnesium


• Meclofenamate


• Mefenamic Acid


• Meloxicam


• Mepindolol


• Metformin


• Methyclothiazide


• Metipranolol


• Metolazone


• Metoprolol


• Nabumetone


• Nadolol


• Naproxen


• Nebivolol


• Nelfinavir


• Nesiritide


• Niflumic Acid


• Nimesulide


• Oxaprozin


• Oxcarbazepine


• Oxprenolol


• Oxyphenbutazone


• Penbutolol


• Phenobarbital


• Phenylbutazone


• Pindolol


• Pirazolac


• Piretanide


• Piroxicam


• Pirprofen


• Polythiazide


• Propranolol


• Propyphenazone


• Proquazone


• Quinethazone


• Quinupristin


• Rifampin


• Rifapentine


• Rofecoxib


• Saquinavir


• Sotalol


• St John's Wort


• Sulindac


• Suprofen


• Talinolol


• Tenidap


• Tenoxicam


• Tertatolol


• Tiaprofenic Acid


• Timolol


• Tolmetin


• Torsemide


• Trichlormethiazide


• Trimethoprim


• Valdecoxib


• Xipamide


• Zomepirac

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.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

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:

• Angioedema (an allergic skin disease), family history of or unknown cause—This medicine should not be used in patients with this condition.

• Bee-sting allergy treatments or


• Dialysis—Increased risk of serious allergic reaction occurring.

• Dehydration—Lowering effects on blood pressure may be increased.

• Diabetes mellitus (sugar diabetes)—Increased risk of potassium levels in the body becoming too high.

• Heart attack or stroke or


• Heart or blood vessel disease or


• Hypotension (low blood pressure)—Further lowering of blood pressure may make problems resulting from these conditions worse.

• Kidney disease or


• Liver disease—Effects may be increased because of slower removal from the body.

• Previous reaction to any ACE inhibitor involving hoarseness; swelling of the face, mouth, hands, or feet; or sudden trouble in swallowing or breathing—Reaction is more likely to occur again.

• Scleroderma or


• Systemic lupus erythematosus (SLE) (or history of)—Increased risk of blood problems caused by ACE inhibitors.

Proper Use of Lexxel

Take this medicine exactly as directed by your doctor, at the same time each day. Do not take more of it and do not take it more often than directed.

Swallow the tablets whole, without breaking, crushing, or chewing them.

If felodipine is taken with grapefruit juice, its effects may be increased. Check with your doctor before taking this medicine with grapefruit juice.

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 high blood pressure:
    
    • Adults—1 tablet once a day to start. Your doctor may increase your dose up to 4 tablets once a day if needed, to equal 20 mg enalapril and 10 mg felodipine extended-release.
    
    
    • 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.

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 Lexxel

It is very important that your doctor check your progress at regular visits. This will allow your doctor to make sure the medicine is working properly, to check for unwanted effects, and to change the dosage if needed.

If you think that you may have become pregnant, check with your doctor immediately. Use of this medicine, especially during the second and third trimesters (after the first 3 months) of pregnancy, may cause serious injury or even death to the unborn child.

Do not take any other medicines, potassium supplements, or salt substitutes that contain potassium unless approved or prescribed by your doctor.

Dizziness, lightheadedness, or fainting may occur after the first dose, especially if you have been taking a diuretic (water pill). Make sure you know how you react to the medicine before you drive, use machines, or do other things that could be dangerous if you experience these effects.

Call your doctor if you faint or feel lightheaded while you are taking this medicine.

Check with your doctor if you notice any signs of fever, sore throat, or chills. These could be symptoms of an infection developing as a result of low white blood cell counts.

Check with your doctor if you notice difficult breathing or swelling of the face, arms, or legs. These could be symptoms of a serious allergic reaction.

Check with your doctor if you become sick while taking this medicine, especially with severe or continuing vomiting or diarrhea. These conditions may cause you to lose too much water, possibly resulting in low blood pressure.

Dizziness, lightheadedness, or fainting may also occur if you exercise or if the weather is hot. Heavy sweating can cause loss of too much water and result in low blood pressure. Use extra care during exercise or hot weather.

Black patients may be less sensitive to the blood pressure-lowering effects of this medicine. In addition, the risk of a serious allergic reaction involving swelling of the face, mouth, hands, or feet may be increased.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine.

Lexxel 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:

Less common

• Dizziness, lightheadedness, or fainting


• swelling of ankles, feet, or lower legs

Rare

• Chills, fever, and sore throat


• swelling of face, mouth, hands, or feet


• trouble in swallowing or breathing (sudden), accompanied by hoarseness


• unusual bleeding or bruising


• yellow eyes or skin

Signs and symptoms of too much potassium in the body

• Confusion


• irregular heartbeat


• nervousness


• numbness or tingling in the hands, feet, or lips


• shortness of breath


• weakness or heaviness of legs

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

• Headache

Less common

• Cough (dry, persistent)


• flushing


• swelling of the gums


• unusual tiredness

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: Lexxel 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 Lexxel resources

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

• Lexxel Prescribing Information (FDA)


• Lexxel Concise Consumer Information (Cerner Multum)


• Lexxel MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Lexxel with other medications

• High Blood Pressure

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
Brands: Chemet

Introduction

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

Uses for Succimer

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}

Succimer 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 Succimer

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 Succimer

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

Succimer 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 Succimer resources

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

• Succimer Professional Patient Advice (Wolters Kluwer)


• Succimer MedFacts Consumer Leaflet (Wolters Kluwer)


• succimer Concise Consumer Information (Cerner Multum)


• succimer Advanced Consumer (Micromedex) - Includes Dosage Information


• Chemet Prescribing Information (FDA)

Compare Succimer with other medications

• Lead Poisoning, Severe

Xyrem 500 mg / ml oral solution

1. Name Of The Medicinal Product

Xyrem 500 mg/ml oral solution

2. Qualitative And Quantitative Composition

Each ml of solution contains 500 mg of sodium oxybate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Oral solution.

The oral solution is clear to slightly opalescent.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of narcolepsy with cataplexy in adult patients.

4.2 Posology And Method Of Administration

Treatment should be initiated by and remain under the guidance of a physician experienced in the treatment of sleep disorders.

Due to the well known potential of abuse of sodium oxybate, physicians should evaluate patients for a history of or susceptibility to drug abuse prior to commencing treatment. During treatment, patients should be monitored for the risk of diversion, misuse and abuse of sodium oxybate (see section 4.4).

Posology The recommended starting dose is 4.5 g/day sodium oxybate divided into two equal doses of 2.25 g/dose. The dose should be titrated to effect based on efficacy and tolerability (see section 4.4) up to a maximum of 9 g/day divided into two equal doses of 4.5 g/dose by adjusting up or down in dose increments of 1.5 g/day (i.e. 0.75 g/dose). A minimum of one to two weeks is recommended between dose increments. The dose of 9 g/day should not be exceeded due to the possible occurrence of severe symptoms at doses of 18 g/day or above (see section 4.4).

Single doses of 4.5 g should not be given unless the patient has been titrated previously to that dose level.

Discontinuation of Xyrem

The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled clinical trials (see section 4.4).

If the patient stops taking the medicinal product for more than 14 consecutive days, titration should be restarted from the lowest dose.

Special populations

Patients with hepatic impairment

The starting dose should be halved in all patients with hepatic impairment, and response to dose increments monitored closely (see section 4.4).

Patients with renal impairment

All patients with impaired renal function should consider a dietary recommendation to reduce sodium intake (see section 4.4).

Elderly patients

Elderly patients should be monitored closely for impaired motor and/or cognitive function when taking sodium oxybate (see section 4.4).

Paediatric population

The safety and efficacy of sodium oxybate in children and adolescents aged 0-18 years has not been established. No data is available. Therefore the use of sodium oxybate in children and adolescents in not recommended.

Method of administration

Xyrem should be taken orally upon getting into bed and again between 2.5 to 4 hours later. It is recommended that both doses of Xyrem should be made up at the same time upon retiring to bed.

Xyrem is provided for use with a graduated measuring syringe and two 90 ml dosing cups with child resistant caps. Each measured dose of Xyrem must be dispensed into the dosing cup and diluted with 60 ml of water prior to ingestion. Because food significantly reduces the bioavailability of sodium oxybate, patients should eat at least several (2-3) hours before taking the first dose of Xyrem at bedtime. Patients should always observe the same timing of dosing in relation to meals.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Patients with major depression

Patients with succinic semialdehyde dehydrogenase deficiency.

Patients being treated with opioids or barbiturates.

4.4 Special Warnings And Precautions For Use

Xyrem has the potential to induce respiratory depression

Respiratory depression

Sodium oxybate also has the potential to induce respiratory depression. Apnoea and respiratory depression have been observed in a fasting healthy subject after a single intake of 4.5 g (twice the recommended starting dose). Patients should be questioned regarding signs of Central Nervous System (CNS) or respiratory depression. Special caution should be observed in patients with an underlying respiratory disorder. Because of the higher risk of sleep apnoea, patients with a BMI

Approximately 80% of patients who received sodium oxybate during clinical trials maintained CNS stimulant use. Whether this affected respiration during the night is unknown. Before increasing the sodium oxybate dose (see section 4.2), prescribers should be aware that sleep apnoea occurs in up to 50% of patients with narcolepsy.

Abuse potential and dependence

Sodium oxybate, which is as the sodium salt of GHB, is a CNS depressant active substance with well known abuse potential. Prior to treatment physicians should evaluate patients for a history of or susceptibility to drug abuse. Patients should be routinely monitored and in the case of suspected abuse, treatment with sodium oxybate should be discontinued.

There have been case reports of dependence after illicit use of GHB at frequent repeated doses (18 to 250 g/day) in excess of the therapeutic dose range. Whilst there is no clear evidence of emergence of dependence in patients taking sodium oxybate at therapeutic doses, this possibility cannot be excluded.

CNS depression

The combined use of alcohol or any CNS depressant medicinal product with sodium oxybate may result in potentiation of the CNS-depressant effects of sodium oxybate. Therefore, patients should be warned against the use of alcohol in conjunction with sodium oxybate.

Patients with porphyria

Sodium oxybate is considered to be unsafe in patients with porphyria because it has been shown to be porphyrogenic in animals or in vitro systems.

Benzodiazepines

Given the possibility of increasing the risk of respiratory depression, the concomitant use of benzodiazepines and sodium oxybate should be avoided

Neuropsychiatric events

Patients may become confused while being treated with sodium oxybate. If this occurs, they should be evaluated fully, and appropriate intervention considered on an individual basis. Other neuropsychiatric events include anxiety, psychosis, paranoia, hallucinations, and agitation. The emergence of thought disorders and/or behavioural abnormalities when patients are treated with sodium oxybate requires careful and immediate evaluation.

The emergence of depression when patients are treated with sodium oxybate requires careful and immediate evaluation. Patients with a previous history of a depressive illness and/or suicide attempt should be monitored especially carefully for the emergence of depressive symptoms while taking sodium oxybate. Major depression is contraindicated for use with Xyrem (section 4.3).

If a patient experiences urinary or faecal incontinence during sodium oxybate therapy, the prescriber should consider pursuing investigations to rule out underlying aetiologies.

Sleepwalking has been reported in patients treated in clinical trials with sodium oxybate. It is unclear if some or all of these episodes correspond to true somnambulism (a parasomnia occurring during non-REM sleep) or to any other specific medical disorder. The risk of injury or self-harm should be borne in mind in any patient with sleepwalking. Therefore, episodes of sleepwalking should be fully evaluated and appropriate interventions considered.

Sodium intake

Patients taking sodium oxybate will have an additional daily intake of sodium that ranges from 0.82 g (for a 4.5 g/day Xyrem dose) to 1.6 g (for a 9 g/day Xyrem dose). A dietary recommendation to reduce sodium intake should be carefully considered in the management of patients with heart failure, hypertension or compromised renal function. (see section 4.2).

Patients with compromised liver function

Patients with compromised liver function will have an increased elimination half-life and systemic exposure to sodium oxybate (see Section 5.2). The starting dose should therefore be halved in such patients, and response to dose increments monitored closely (see section 4.2).

Elderly

There is very limited experience with sodium oxybate in the elderly. Therefore, elderly patients should be monitored closely for impaired motor and/or cognitive function when taking sodium oxybate.

Childhood and adolescence

Safety and effectiveness in children and adolescents has not been established, therefore use in patients under 18 years of age is not recommended.

Epileptic patients

Seizures have been observed in patients treated with sodium oxybate. In patients with epilepsy, the safety and efficacy of sodium oxybate has not been established, therefore use is not recommended.

Rebound effects and withdrawal syndrome

The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled clinical trials. In some patients, cataplexy may return at a higher frequency on cessation of sodium oxybate therapy, however this may be due to the normal variability of the disease. Although the clinical trial experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses does not show clear evidence of a withdrawal syndrome, in rare cases, events such as insomnia, headache, anxiety, dizziness, sleep disorder, somnolence, hallucination, and psychotic disorders were observed after GHB discontinuation.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The combined use of alcohol with sodium oxybate may result in potentiation of the central nervous system-depressant effects of sodium oxybate. Patients should be warned against the use of any alcoholic beverages in conjunction with sodium oxybate.

Sodium oxybate should not be used in combination with sedative hypnotics or other CNS depressants.

Sedative hypnotics

Drug interaction studies in healthy adults with sodium oxybate (single dose of 2.25 g) and lorazepam (an anxiolytic [benzodiazepine]; single dose of 2 mg) and zolpidem tartrate (a hypnotic [non-benzodiazepine]; single dose of 5 mg) demonstrated no pharmacokinetic interactions. Increased sleepiness was observed after concomitant administration of sodium oxybate (2.25 g) and lorazepam (2 mg). The pharmacodynamic interaction with zolpidem has not been assessed. When higher doses up to 9 g/d of sodium oxybate are combined with higher doses of hypnotics (within the recommended dose range) pharmacodynamic interactions associated with symptoms of CNS depression and/or respiratory depression cannot be excluded (see section 4.3).

Tramadol

A drug interaction study in healthy adults with sodium oxybate (single dose of 2.25 g) and tramadol (a central acting opioid; single dose of 100 mg) demonstrated no pharmacokinetic/pharmacodynamic interaction. When higher doses up to 9 g/d of sodium oxybate are combined with higher doses of opioids (within the recommended dose range) pharmacodynamic interactions associated with symptoms of CNS depression and/or respiratory depression cannot be excluded (see sections 4.3).

Antidepressants

Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between sodium oxybate (single dose of 2.25 g) and the antidepressants protriptyline hydrochloride (single dose of 10 mg) and duloxetine (60 mg at steady state). No additional effect on sleepiness was observed when comparing single doses of sodium oxybate alone (2.25 g) and sodium oxybate (2.25 g) in combination with duloxetine (60 mg at steady state). Antidepressants have been used in the treatment of cataplexy. A possible additive effect of antidepressants and sodium oxybate cannot be excluded. The rate of adverse events has increased when sodium oxybate is co-administered with tricyclic antidepressants.

Modafinil

A drug interaction study in healthy adults demonstrated no pharmacokinetic interactions between sodium oxybate (single dose of 4.5 g) and modafinil (a stimulant; single dose of 200 mg). Sodium oxybate has been administered concomitantly with CNS stimulant agents in approximately 80% of patients in clinical studies in narcolepsy. Whether this affected respiration during the night is unknown.

The co-administration of omeprazole (a medicinal product that alters gastric pH) has no clinically significant effect on the pharmacokinetics of sodium oxybate. The dose of sodium oxybate therefore does not require adjustment when given concomitantly with proton pump inhibitors.

Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does not significantly inhibit the activities of the human isoenzymes (see section 5.2).

Since sodium oxybate is metabolised by GHB dehydrogenase there is a potential risk of an interaction with medicinal products that stimulate or inhibit this enzyme (e.g. valproate, phenytoin or ethosuximide). No interaction studies have been conducted in human subjects.

4.6 Pregnancy And Lactation

Pregnancy

Animal studies have shown no evidence of teratogenicity but embryolethality was seen in both rat and rabbit studies (see section 5.3).

Data from a limited number of pregnant women exposed in the first trimester indicate a possible increased risk of spontaneous abortions. To date no other relevant epidemiological data are available. Limited data from pregnant patients during second and third trimester indicate no malformative nor foeto/neonatal toxicity of sodium oxybate.

Sodium oxybate is not recommended during pregnancy.

Breastfeeding

It is not known whether sodium oxybate and/or its metabolites are excreted into breast milk. Breastfeeding is not recommended during treatment with sodium oxybate.

Fertility

There is no clinical data available on the effect of sodium oxybate on fertility. No effect on fertility parameters in the rat were observed (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

Sodium oxybate has a major influence on the ability to drive and use machines.

For at least 6 hours after taking sodium oxybate, patients must not undertake activities requiring complete mental alertness or motor co-ordination, such as operating machinery or driving.

When patients first start taking sodium oxybate, until they know whether this medicinal product will still have some carryover effect on them the next day, they should use extreme care while driving a car, operating heavy machines, or performing any other task that could be dangerous or require full mental alertness.

4.8 Undesirable Effects

The most commonly reported adverse reactions are dizziness, nausea, and headache, all occurring in 10% to 20% of patients.

Frequency estimate: very common (

Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

Immune system disorders:

Uncommon : hypersensitivity

Metabolism and nutrition disorders:

Common: anorexia, decreased appetite

Psychiatric disorders:

Common: depression, cataplexy, anxiety, abnormal dreams, confusional state, disorientation, nightmares, sleepwalking, sleep disorder, insomnia, middle insomnia, nervousness

Uncommon: suicide attempt, psychosis, paranoia, hallucination, abnormal thinking, agitation, initial insomnia

Not known (cannot be estimated from the available data): suicidal ideation

Nervous system disorders:

Very common: dizziness, headache

Common: sleep paralysis, somnolence, tremor, balance disorder, disturbance in attention, hypoaesthesia, paraesthesia, sedation, dysgeusia

Uncommon: myoclonus, amnesia, restless legs syndrome

Not known (cannot be estimated from the available data): convulsion

Ear and labyrinth disorders:

Common: vertigo

Eye disorders:

Common: blurred vision

Cardiac disorders:

Common: palpitations

Vascular disorders:

Common: hypertension

Respiratory, thoracic and mediastinal disorders:

Common: dyspnoea, snoring, nasal congestion

Not known (cannot be estimated from the available data): respiratory depression, sleep apnoea

Gastrointestinal disorders:

Very common: nausea (the frequency of nausea is higher in women than men)

Common: vomiting, diarrhoea, abdominal pain upper,

Uncommon: faecal incontinence

Skin and subcutaneous tissue disorders:

Common: hyperhidrosis, rash

Not known (cannot be estimated from the available data): urticaria

Musculoskeletal, connective tissue and bone disorders:

Common: arthralgia, muscle, spasms, back pain

Renal and urinary disorders:

Common: enuresis nocturna, urinary incontinence

General disorders and administration site conditions:

Common: asthenia, fatigue, feeling drunk, oedema peripheral

Infections and infestations:

Common: nasopharyngitis, sinusitis

Investigations:

Common: blood pressure increased, weight decreased

Injury, poisoning and procedural complications

Common: fall

Description of selected adverse reactions

In some patients, cataplexy may return at a higher frequency on cessation of sodium oxybate therapy, however this may be due to the normal variability of the disease. Although the clinical trial experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses does not show clear evidence of a withdrawal syndrome, in rare cases, adverse reactions such as insomnia, headache, anxiety, dizziness, sleep disorder, somnolence, hallucination, and psychotic disorders were observed after GHB discontinuation.

4.9 Overdose

Information about signs and symptoms associated with overdose with sodium oxybate is limited. Most data derives from the illicit use of GHB. Sodium oxybate is the sodium salt of GHB. Events associated with withdrawal syndrome have been observed outside the therapeutic range.

Patients have exhibited varying degrees of depressed consciousness that may fluctuate rapidly between a confusional, agitated combative state with ataxia and coma. Emesis (even with impaired consciousness), diaphoresis, headache, and impaired psychomotor skills may be observed. Blurred vision has been reported. An increasing depth of coma has been observed at higher doses. Myoclonus and tonic-clonic seizures have been reported. There are reports of compromise in the rate and depth of respiration and of life-threatening respiratory depression, necessitating intubation and ventilation. Cheyne-Stokes respiration and apnoea have been observed. Bradycardia and hypothermia may accompany unconsciousness, as well as muscular hypotonia, but tendon reflexes remain intact. Bradycardia has been responsive to atropine intravenous administration.

Gastric lavage may be considered if co-ingestants are suspected. Because emesis may occur in the presence of impaired consciousness, appropriate posture (left lateral recumbent position) and protection of the airway by intubation may be warranted. Although gag reflex may be absent in deeply comatose patients, even unconscious patients may become combative to intubation, and rapid sequence induction (without the use of sedative) should be considered.

No reversal of the central depressant effects of sodium oxybate can be expected from flumazenil administration. There is insufficient evidence to recommend the use of naloxone in the treatment of overdose with GHB. The use of haemodialysis and other forms of extracorporeal medicinal product removal have not been studied in sodium oxybate overdose. However, due to the rapid metabolism of sodium oxybate, these measures are not warranted.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other nervous system medicinal products, ATC code: N07XX04.

Sodium oxybate is a central nervous system depressant which reduces excessive daytime sleepiness and cataplexy in patients with narcolepsy and modifies sleep architecture reducing fragmented nighttime sleep. The precise mechanism by which sodium oxybate produces an effect is unknown, however sodium oxybate is thought to act by promoting slow (delta) wave sleep and consolidating night-time sleep. Sodium oxybate administered before nocturnal sleep increases Stages 3 and 4 sleep and increases sleep latency, whilst reducing the frequency of sleep onset REM periods (SOREMPs). Other mechanisms, which have yet to be elucidated, may also be involved. In the clinical trial database, greater than 80 % of patients maintained concomitant stimulant use.

The effectiveness of sodium oxybate for the treatment of narcolepsy symptoms was established in four multicentre, randomised, double-blind, placebo-controlled, parallel-group trials (Trial 1, 2, 3 and 4) in patients with narcolepsy with cataplexy except for trial 2 where cataplexy was not required for enrolment Concomitant stimulant use was permitted in all trials (except for the active-treatment phase of Trial 2); antidepressants were withdrawn prior to active treatment in all trials with the exception of Trial 2. In each trial, the daily dose was divided into two equal doses. The first dose each night was taken at bedtime and the second dose was taken 2.5 to 4 hours later.

Table 1 Summary of clinical trials performed using sodium oxybate for the treatment of narcolepsy

Trial	Primary Efficacy	N=	Secondary Efficacy	Duration	Active treatment and Dose (g/d)
Trial 1	EDS (ESS); CGIc	246	MWT/Sleep Architecture/Cataplexy/Naps/FOSQ	8 weeks	Xyrem 4.5 - 9
Trial 2	EDS (MWT)	231	Sleep Architecture/ESS/CGIc/Naps	8 weeks	Xyrem 6 - 9 Modafinil 200-600 mg
Trial 3	Cataplexy	136	EDS (ESS)/CGIc/Naps	4 weeks	Xyrem 3 - 9
Trial 4	Cataplexy	55	None	4 weeks	Xyrem 3 - 9

EDS - Excessive daytime sleepiness; ESS - Epworth Sleepiness Scale; MWT - Maintenance of Wakefulness Test; Naps - Number of inadvertent daytime naps; CGIc - Clinical Global Impression of Change; FOSQ - Functional Outcomes of Sleep Questionnaire

Trial 1 enrolled 246 patients with narcolepsy and incorporated a 1 week up-titration period. The primary measures of efficacy were changes in excessive daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS), and the change in the overall severity of the patient's narcolepsy symptoms as assessed by the investigator using the Clinical Global Impressions of Change (CGI-c) measure.

Table 2 Summary of ESS in Trial 1

Epworth Sleepiness Scale (ESS; range 0-24)
Dose Group [g/d (n)]	Baseline	Endpoint	Median Change from Baseline	Change from Baseline Compared to Placebo (p-value)
Placebo (60)	17.3	16.7	-0.5	-
4.5 (68)	17.5	15.7	-1.0	0.119
6 (63)	17.9	15.3	-2.0	0.001
9 (55)	17.9	13.1	-2.0	< 0.001

Table 3 Summary of CGI-c in Trial 1

Clinical Global Impressions of Change (CGI-c)
Dose Group [g/d (n)]	Responders* N (%)	Change from Baseline Compared to Placebo (p-value)
Placebo (60)	13 (21.7)	-
4.5 (68)	32 (47.1)	0.002
6 (63)	30 (47.6)	< 0.001
9 (55)	30 (54.4)	< 0.001

* The CGI-c data were analysed by defining responders as those patients who were very much improved or much improved.

Trial 2 compared the effects of orally administered sodium oxybate, modafinil and sodium oxybate + modafinil, with placebo in the treatment of daytime sleepiness in narcolepsy. During the 8 week double-blind period, patients took modafinil at their established dose or placebo equivalent. The sodium oxybate or placebo equivalent dose was 6 g/day for the first 4 weeks and was increased to 9 g/day for the remaining 4 weeks. The primary measure of efficacy was excessive daytime sleepiness as measured by objective response in MWT.

Table 4 Summary of MWT in Trial 2

TRIAL 2
Dose Group	Baseline	Endpoint	Mean Change from Baseline	Endpoint Compared to Placebo
Placebo (56)	9.9	6.9	-2.7	-
Sodium Oxybate (55)	11.5	11.3	0.16	<0.001
Modafinil (63)	10.5	9.8	-0.6	0.004
Sodium Oxybate + Modafinil (57)	10.4	12.7	2.3	<0.001

Trial 3 enrolled 136 narcoleptic patients with moderate to severe cataplexy (median of 21 cataplexy attacks per week) at baseline. The primary efficacy measure in this trial was the frequency of cataplexy attacks.

Table 5 Summary of outcomes in Trial 3

Dosage	Number of Subjects	Cataplexy Attacks
Trial 3	Baseline	Median Change from Baseline	Change from Baseline Compared to Placebo (p-value)
		Median attacks/week
Placebo	33	20.5	-4	-
3.0 g/day	33	20.0	-7	0.5235
6.0 g/day	31	23.0	-10	0.0529
9.0 g/day	33	23.5	-16	0.0008

Trial 4 enrolled 55 narcoleptic patients who had been taking open-label sodium oxybate for 7 to 44 months. Patients were randomised to continued treatment with sodium oxybate at their stable dose or to placebo. Trial 4 was designed specifically to evaluate the continued efficacy of sodium oxybate after long-term use. The primary efficacy measure in this trial was the frequency of cataplexy attacks.

Table 6 Summary of outcome in Trial 4

	Number of Subjects	Baseline	Median Change from Baseline	Change from Baseline Compared to Placebo (p-value)
Trial 4	Median attacks/two weeks
Placebo	29	4.0	21.0	-
Sodium oxybate	26	1.9	0	p <0.001

In Trial 4, the response was numerically similar for patients treated with doses of 6 to 9 g/day, but there was no effect seen in patients treated with doses less than 6 g/day.

5.2 Pharmacokinetic Properties

Sodium oxybate is rapidly and almost completely absorbed after oral administration; absorption is delayed and decreased by a high fat meal. It is eliminated mainly by metabolism with a half-life of 0.5 to 1 hour. Pharmacokinetics are nonlinear with the area under the plasma concentration curve (AUC) versus time curve increasing 3.8-fold as dose is doubled from 4.5 g to 9 g. The pharmacokinetics are not altered with repeat dosing.

Absorption: Sodium oxybate is absorbed rapidly following oral administration with an absolute bioavailability of about 88 %. The average peak plasma concentrations (1^st and 2^nd peak) following administration of a 9 g daily dose divided into two equivalent doses given four hours apart were 78 and 142 μg/ml, respectively. The average time to peak plasma concentration (T_max) ranged from 0.5 to 2 hours in eight pharmacokinetic studies. Following oral administration, the plasma levels of sodium oxybate increase more than proportionally with increasing dose. Single doses greater than 4.5 g have not been studied. Administration of sodium oxybate immediately after a high fat meal resulted in delayed absorption (average T_max increased from 0.75 hr to 2.0 hr) and a reduction in peak plasma level (C_max) by a mean of 58% and of systemic exposure (AUC) by 37%.

Distribution: Sodium oxybate is a hydrophilic compound with an apparent volume of distribution averaging 190-384 ml/kg. At sodium oxybate concentrations ranging from 3 to 300 μg/ml, less than 1% is bound to plasma proteins.

Biotransformation: Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by β-oxidation. The primary pathway involves a cytosolic NADP⁺-linked enzyme, GHB dehydrogenase, that catalyses the conversion of sodium oxybate to succinic semialdehyde, which is then biotransformed to succinic acid by the enzyme succinic semialdehyde dehydrogenase. Succinic acid enters the Krebs cycle where it is metabolised to carbon dioxide and water. A second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyses the conversion to succinic semialdehyde in the presence of α-ketoglutarate. An alternate pathway of biotransformation involves β-oxidation via 3,4-dihydroxybutyrate to Acetyl CoA, which also enters the citric acid cycle to result in the formation of carbon dioxide and water. No active metabolites have been identified.

Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does not significantly inhibit the activities of the human isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A up to the concentration of 3 mM (378 μg/ml). These levels are considerably higher than levels achieved with therapeutic doses.

Elimination: The clearance of sodium oxybate is almost entirely by biotransformation to carbon dioxide, which is then eliminated by expiration. On average, less than 5% of unchanged medicinal product appears in human urine within 6 to 8 hours after dosing. Faecal excretion is negligible.

Special populations:

Elderly patients:. In a limited number of patients greater than the age of 65 years the pharmacokinetics of sodium oxybate was not different compared to patients younger than 65 years of age.

Paediatric patients: The pharmacokinetics of sodium oxybate in paediatric patients under the age of 18 years have not been studied.

Renal impairment: Because the kidney does not have a significant role in the excretion of sodium oxybate, no pharmacokinetic study in patients with renal dysfunction has been conducted; no effect of renal function on sodium oxybate pharmacokinetics would be expected.

Hepatic disease: Sodium oxybate undergoes significant presystemic (hepatic first-pass) metabolism. After a single oral dose of 25 mg/kg, AUC values were double in cirrhotic patients, with apparent oral clearance reduced from 9.1 in healthy adults to 4.5 and 4.1 ml/min/kg in Class A (without ascites) and Class C (with ascites) patients, respectively. Elimination half-life was significantly longer in Class C and Class A patients than in control subjects (mean t_1/2 of 59 and 32 versus 22 minutes). It is prudent to reduce the starting dose of sodium oxybate by one-half in patients with liver dysfunction (see Section 4.2).

Race

The effect of race on metabolism of sodium oxybate has not been evaluated.

5.3 Preclinical Safety Data

Repeat administration of sodium oxybate to rats (90 days and 26 weeks) and dogs (52 weeks) did not result in any significant findings in clinical chemistry and micro- and macro pathology. Treatment-related clinical signs were mainly related to sedation, reduced food consumption and secondary changes in body weight, body weight gain and organ weights. The rat and dog exposures at the NOEL were lower (~50%) than that in humans. Sodium oxybate was non-mutagenic and non-clastogenic in in vitro and in vivo assays.

Gamma Butyrolactone (GBL), a pro-drug of GHB tested at exposures similar to the expected in man (1.21-1.64 times) has been classified by NTP as non-carcinogenic in rats and equivocal carcinogen in mice, due to slight increase of pheochromocytomas which was difficult to interpret due to high mortality in the high dose group. In a rat carcinogenicity study with oxybate no compound-related tumours were identified.

GHB had no effect on mating, general fertility or sperm parameters and did not produce embryo-foetal toxicity in rats exposed to up 1000 mg/kg/day GHB (1.64 times the human exposure calculated in nonpregnant animals). Perinatal mortality was increased and mean pup weight was decreased during the lactation period in high-dose F₁ animals. The association o

Calmurid Cream

1. Name Of The Medicinal Product

Calmurid 10%/5% w/w Cream

2. Qualitative And Quantitative Composition

One gram of cream contains 100 mg of Urea and 50 mg of Lactic acid

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Cream

A homogenous, white, oil-in-water cream

4. Clinical Particulars

4.1 Therapeutic Indications

To be applied topically for the correction of hyperkeratosis and dryness in ichthyosis and allied conditions characterised by dry, rough, scaly skin.

4.2 Posology And Method Of Administration

For external use only.

Adults, elderly and children:

A thick layer of Calmurid is applied twice daily after washing the affected area. The cream is left on the skin for 3-5 minutes and then rubbed lightly in. Excess cream should be wiped off the skin with a tissue, not washed off. Frequency of application can be reduced as the patient progresses. In hyperkeratosis of the feet apply Calmurid as above after soaking the feet in warm water for 15 minutes and drying with a rough towel.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients

4.4 Special Warnings And Precautions For Use

Calmurid is acidic and hypertonic and can cause smarting if applied to raw areas, fissures or mucous membranes. Where this is a barrier to therapy the use of Calmurid diluted 50% with aqueous cream B.P. for one week should result in freedom from smarting upon use of Calmurid.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Low pH of cream might affect stability of other drugs.

4.6 Pregnancy And Lactation

There is no specific data available regarding the use in pregnant women and during lactation.

4.7 Effects On Ability To Drive And Use Machines

Calmurid has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Calmurid is acidic and hypertonic and can cause smarting if applied to raw areas, fissures or mucous membranes.

4.9 Overdose

Unlikely. In the case of smarting, wash the cream off.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Carbomide products

ATC code: D02AE

Urea at a concentration of 10% has keratolytic, anti microbial, anti pruritic and hydrating effects on the skin. Lactic acid has keratolytic, hydrating and anti microbial properties also. Treatment of ichthyotic patients shows a parallel between clinical improvement and increase in the otherwise depressed binding capacity of the horny layer.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber, which are additional to those already included in other sections of the SmPC

6. Pharmaceutical Particulars

6.1 List Of Excipients

Glyceryl Monostearate

Betaine Monohydrate

Diethanolamine Cetylphosphate (``Amphisol'')

Hard Fat

Cholesterol

Sodium chloride

Purified water

6.2 Incompatibilities

The low pH due to lactic acid means care in choice of other packages or other drugs admixed.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25°C. Do not refrigerate or freeze.

6.5 Nature And Contents Of Container

Tubes

White low density polyethylene tubes fitted with white polypropylene screw caps

Package sizes: 15, 20, 30, 50, 100 g.

Pump dispenser

White polypropylene bottle fitted with a white polyethylene closure and a natural polyethylene follower plate.

Package sizes: 400, 500 g.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not relevant.

7. Marketing Authorisation Holder

Galderma (UK) Limited

Meridien House

69-71 Clarendon Road

Watford

Herts.

WD17 1DS

UK

8. Marketing Authorisation Number(S)

PL 10590/0009

9. Date Of First Authorisation/Renewal Of The Authorisation

9 February 1993

10. Date Of Revision Of The Text

December 2008