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Monday, September 12, 2016

Zavesca

Generic Name: Miglustat
Class: Other Miscellaneous Therapeutic Agents
VA Class: HS900
Chemical Name: 1-Butyl-2-(hydroxymethyl)piperidine-3,4,5-triol
Molecular Formula: C₁₀H₂₁NO₄
CAS Number: 72599-27-0

Introduction

Glucosylceramide synthase (ceramide glucosyltransferase) inhibitor; decreases glucocerebroside accumulation in macrophages and some manifestations (hepatomegaly, splenomegaly) of type 1 Gaucher’s disease.¹ ¹⁵ ¹⁹ ²⁰ ²¹

Uses for Zavesca

Gaucher’s Disease

Management of mild to moderate nonneuronopathic (type 1) Gaucher’s disease in adults for whom enzyme replacement therapy is unsuitable (e.g., because of allergy, hypersensitivity, poor venous access).¹

Safety and efficacy not established in patients with severe type 1 Gaucher’s disease (i.e., hemoglobin <9 g/dL, platelet count <50,000/mm³, or active bone disease).¹

Designated an orphan drug by the FDA for the management of Gaucher’s disease.¹⁸

Enzyme replacement therapy with alglucerase or imiglucerase is current treatment of choice for type 1 Gaucher’s disease.¹ ² ³ ⁴ ⁶ ⁷ ¹¹ ¹² ¹³ ¹⁴ ¹⁶

Zavesca Dosage and Administration

General

If a dose is missed, that dose should be skipped and the next dose taken at the usual time.¹

Reduced dosage may be necessary in some patients because of adverse effects (e.g., diarrhea, tremor).¹ ¹⁶

Administration

Oral Administration

Administer 3 times daily at regular intervals, without regard to meals.¹

Dosage

Adults

Gaucher’s Disease

Oral

100 mg 3 times daily.¹ ¹⁶

Reduce dosage to 100 mg once or twice daily if necessary because of adverse effects.¹ ¹⁶

Special Populations

Renal Impairment

Dosage in Renal Impairment
Cl_cr (mL/min)	Initial dosage
50–70	100 mg twice daily¹
30–50	100 mg once daily¹
<30	Use not recommended¹

Geriatric Patients

Select dosage with caution because of possible age-related decreases in renal, hepatic, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Zavesca

Contraindications

Known hypersensitivity to miglustat or any ingredient in the formulation.¹

Women who are or may become pregnant.¹

Warnings/Precautions

Warnings

Peripheral Neuropathy

Peripheral neuropathy reported; monitor all patients with neurologic evaluation at baseline and every 6 months while on therapy.¹

If symptoms (e.g., numbness, tingling) occur, reassess risk versus benefit of therapy; consider discontinuance.¹

General Precautions

Therapy should be directed by clinicians knowledgeable in the management of Gaucher’s disease.¹

Tremor

Tremor or exaggerated physiologic hand tremor reported in about 30% of patients.¹ ²⁴

Usually began within the first month, often resolved between month 1 and 3 of treatment.¹

Dosage reduction may ameliorate tremor, usually within days; drug discontinuance occasionally necessary.¹

Diarrhea and Weight Loss

Diarrhea in approximately 85% of patients studied; associated with increased use of antidiarrheal drugs, usually loperamide.¹ ²⁴

Apparently osmotic in nature, resulting from inhibition of disaccharidase; incidence decreases over time with continued use.¹

Patients should avoid foods with high carbohydrate content.¹

Weight loss in up to 65% of patients studied, generally during first 12 months of therapy.¹

Weight loss may result from diarrhea and associated GI complaints, decreased food intake, or a combination of these and other factors.¹

Effect on Fertility in Males

Adversely affects spermatogenesis and sperm parameters; decreases fertility (rats).¹

All males should use effective birth control while on therapy.¹

Before attempting conception, discontinue therapy and maintain effective contraceptive methods for 3 months.¹

Specific Populations

Pregnancy

Category X.¹ (See Contraindications under Cautions.)

Lactation

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

Pediatric Use

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

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently from younger adults; select dosage with caution.¹

Renal Impairment

Dosage adjustments necessary based on degree of renal impairment; do not use in severe renal impairment. (See Renal Impairment under Dosage and Administration.) ¹

Common Adverse Effects

Diarrhea, flatulence, abdominal pain, abdominal distension with or without gas, nausea, vomiting, bloating, anorexia, dyspepsia, epigastric pain (not related to food), constipation, dry mouth, weight loss, headache, tremor, dizziness, unsteady gait, leg cramps, cramps, back pain, paresthesia, heaviness in limbs, generalized weakness, migraine, visual disturbance, memory loss, thrombocytopenia, menstrual disorder.¹ ²⁴

Interactions for Zavesca

Drugs Metabolized by Hepatic Microsomal Enzymes

No evidence of metabolism in humans; pharmacokinetic interactions unlikely.¹

Specific Drugs

Drug	Interaction	Comments
Imiglucerase	Possible decreased plasma imiglucerase concentrations ¹ Possible decreased peak plasma miglustat concentrations (22%) and AUC (14%) ¹	Concomitant use increased imiglucerase clearance by 70%; results inconclusive (small number of patients studied, variable imiglucerase dosages)¹ Effect on miglustat pharmacokinetics not considered clinically important¹ Combination use not indicated¹
Loperamide	Pharmacokinetic interaction unlikely¹	Concomitant administration apparently did not substantially alter pharmacokinetics of miglustat¹

Zavesca Pharmacokinetics

Absorption

Food

Food decreases the rate but not the extent of absorption.¹

Distribution

Extent

Distributed into extravascular tissues.¹

Not known whether miglustat crosses the placenta or is distributed into milk.¹

Plasma Protein Binding

Does not bind to plasma proteins.¹

Elimination

Metabolism

No evidence of metabolism in humans.¹

Elimination Route

Excreted unchanged in urine.¹ ¹⁵

Half-life

6–7 hours.¹ ¹⁵

Special Populations

In patients with mild, moderate, or severe renal impairment, miglustat clearance is reduced by approximately 40, 60, or ≥70%, respectively.¹ ¹⁵

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).¹

ActionsActions

N-alkylated imino sugar; competitive and reversible inhibitor of ceramide glucosyltransferase (glucosylceramide synthase), which catalyzes the formation of glucosylceramide (glucocerebroside).¹ ¹⁵

Inhibits the formation of glucocerebroside, substrate for glucocerebrosidase enzyme deficient in type 1 Gaucher’s disease.¹ ¹⁵

Substrate reduction therapy with miglustat allows residual activity of deficient endogenous glucocerebrosidase to be more effective, decreasing glucocerebroside accumulation in macrophages;¹ ¹⁵ ¹⁹ ²⁰ decreases hepatomegaly and splenomegaly but has limited effect on increasing hemoglobin and platelet counts in patients with type 1 Gaucher’s disease.¹ ¹⁵ ²¹

Actions are unlike those of enzyme replacement therapy, which increases glucocerebroside degradation in macrophages to reduce manifestations of Gaucher’s disease.¹ ² ³ ⁴ ⁶ ⁷ ¹¹ ¹² ¹³ ¹⁴ ¹⁵ ¹⁶

In type 1 Gaucher’s disease, lipid-engorged macrophages infiltrate the viscera (especially liver and spleen), lymph nodes, and bone marrow, resulting in lipidosis and clinical manifestations of hepatosplenomegaly, anemia, thrombocytopenia, and bone lesions in severe disease.² ³ ⁶ ⁷ ⁸ ⁹ ¹⁰ ¹³ ¹⁵

Advice to Patients

Importance of informing patients of risks and benefits of miglustat therapy, and about alternative therapy (e.g., enzyme replacement therapy).¹

Importance of advising patients that diarrhea and other adverse GI effects and weight loss are common, and to adhere to dietary instructions.¹

Importance of informing clinician of any numbness, pain, or burning in the hands or feet and of the occurrence or worsening of tremor.¹

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and, if pregnancy occurs, to advise woman of risk to the fetus.¹

Importance of men using effective birth control methods during miglustat use and for 3 months following discontinuance of the drug.¹

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.¹

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

Preparations

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

Miglustat
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	100 mg	Zavesca	Actelion

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 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Actelion Pharmaceuticals. Zavesca (miglustat) capsules prescribing information. South San Francisco, CA; 2003 Jul 31.

2. Beutler E. Gaucher’s disease. N Engl J Med. 1991; 325:1354-60. [IDIS 287428] [PubMed 1922238]

3. Anon. Alglucerase for Gaucher’s disease. Med Lett Drugs Ther. 1991; 33:82. [PubMed 1865852]

4. Elstein D, Abrahamov A, Hadas-Halpern I et al. Low-dose low-frequency imiglucerase as a starting regimen of enzyme replacement therapy for patients with type I Gaucher disease. QJM. 1998; 91:483-8. [PubMed 9797931]

5. Elstein D, Abrahamov A, Hadas-Halpern I et al. Gaucher’s Disease. Lancet. 2001; 358:324-7. [IDIS 467174] [PubMed 11498237]

6. Genzyme Corporation. Cerezyme (imiglucerase) prescribing information. Cambridge, MA; 2003 Mar.

7. Barton NW, Furbish FS, Murray GJ et al. Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci USA. 1990; 87:1913-6. [PubMed 2308952]

8. Brady RO, Kanfer JN, Shapiro D. Metabolism of glucocerebrosides: II. Evidence of an enzymatic deficiency in Gaucher’s disease. Biochem Biophys Res Commun. 1965; 18:221-5. [PubMed 14282020]

9. Britton DE, Leinikki PO, Barranger JA et al. Gaucher’s disease: lack of antibody response to intravenous glucocerebrosidase. Life Sci. 1978; 23:2517-20. [PubMed 732537]

10. Basu A, Prence E, Garrett K et al. Comparison of N-acyl phosphatidylethanolamines with different N-acyl groups as activators of glucocerebrosidase in various forms of Gaucher’s disease. Arch Biochem Biophys. 1985; 243:28-34. [PubMed 3933429]

11. Genzyme Corporation. Ceredase (alglucerase) prescribing information. Cambridge, MA; 1992 Feb.

12. Reviewers’ comments (personal observations) on alglucerase.

13. Weinreb NJ, Charrow J, Andersson HC et al. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Register. Am J Med. 2002; 113:112-9. [IDIS 484109] [PubMed 12133749]

14. Niederau C, Haussinger D. Gaucher’s disease: a review for the internist and hepatologist. Hepatogastroenterology. 2000; 47:984-7. [PubMed 11020862]

15. McCormack PL, Goa KL. Miglustat. Drugs. 2003;63:2427-34.

16. Grabowski GA, Barton NW, Pastores G et al. Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase form natural and recombinant sources. Ann Intern Med. 1995; 122:33-9. [IDIS 339881] [PubMed 7985893]

17. Genzyme Corporation, Cambridge, MA. Personal observation on alglucerase.

18. Food and Drug Administration. Cumulative list of orphan drugs designated and/or approved. Rockville, MD; 2004, Aug 31. From FDA web site (http: / / www.fda.gov / ForIndustry / DevelopingProductsforRareDiseasesConditions / HowtoapplyforOrphanProductDesignation / default.htm).

19. Lachmann RH, Platt FM. Substrate reduction therapy for glycosphingolipid storage disorders. Expert Opin Invest Drugs. 2001; 10:455-66.

20. Pastores GM, Barnett NL. Substrate reduction therapy: miglustat as a remedy for symptomatic patients with Gaucher disease type 1. Expert Opin Invest Drugs. 2003; 23:273-81.

21. Cox T, Lachmann R, Hollak C et al. Novel oral treatment of Gaucher’s disease with N-butyldeoxynojirimycin. (OGT 918) to decrease substrate biosynthesis. Lancet. 2000; 355:1481-5. [IDIS 446631] [PubMed 10801168]

22. Heitner R, Elstein D, Aerts J et al. Low-dose N-butyldeoxynojirimycin. (OGT 918) for type 1 Gaucher disease. Blood Cells Mol Dis. 2002; 28:127-33. [PubMed 12064906]

23. Oxford GlycoSciences Plc. Oxford GlycoSciences Plc swith/combination study 004 results on Vevesca (OGT 918) presented at EWGGD [media release]. 2002 May 2.

24. Actelion. South San Francisco, CA: Personal communication.

More Zavesca resources

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

Zavesca Prescribing Information (FDA)

Zavesca Consumer Overview

Zavesca Advanced Consumer (Micromedex) - Includes Dosage Information

Zavesca MedFacts Consumer Leaflet (Wolters Kluwer)

Miglustat Professional Patient Advice (Wolters Kluwer)

Compare Zavesca with other medications

Gaucher Disease

Z-COF 12 Suspension

Pronunciation: DEX-troe-meth-OR-fan/gwye-FEN-e-sin/SOO-doe-e-FED-rin
Generic Name: Dextromethorphan/Guaifenesin/Pseudoephedrine
Brand Name: Z-COF 12

Z-COF 12 Suspension is used for:

Relieving congestion, cough, and throat and airway irritation due to colds, flu, or hay fever. It may also be used for other conditions as determined by your doctor.

Z-COF 12 Suspension is a decongestant, cough suppressant, and expectorant combination. It works by constricting blood vessels, reducing swelling in the nasal passages, and loosening mucus and lung secretions in the chest, making coughs more productive. The cough suppressant works in the brain to help decrease the cough reflex.

Do NOT use Z-COF 12 Suspension if:

you are allergic to any ingredient in Z-COF 12 Suspension

you have severe high blood pressure, rapid heartbeat, or other severe heart problems (eg, heart blood vessel disease)

you have taken furazolidone or a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) within the last 14 days

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

Before using Z-COF 12 Suspension:

Some medical conditions may interact with Z-COF 12 Suspension. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

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

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

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

if you have a history of glaucoma, enlarged prostate gland or other prostate problems, heart problems, diabetes, high blood pressure, blood vessel problems, adrenal gland problems, an overactive thyroid, seizures, or stroke

if you have a chronic cough, chronic obstructive pulmonary disease (COPD), or other lung problems (eg, asthma, chronic bronchitis, emphysema), or if your cough produces large amounts of mucus

Some MEDICINES MAY INTERACT with Z-COF 12 Suspension. Tell your health care provider if you are taking any other medicines, especially any of the following:

Beta-blockers (eg, propranolol), catechol-O-methyltransferase (COMT) inhibitors (eg, tolcapone), furazolidone, indomethacin, MAOIs (eg, phenelzine), or tricyclic antidepressants (eg, amitriptyline) because they may increase the risk Z-COF 12 Suspension's side effects

Digoxin or droxidopa because the risk of irregular heartbeat or heart attack may be increased

Bromocriptine because the risk of its side effects may be increased by Z-COF 12 Suspension

Guanadrel, guanethidine, mecamylamine, methyldopa, or reserpine because their effectiveness may be decreased by Z-COF 12 Suspension

This may not be a complete list of all interactions that may occur. Ask your health care provider if Z-COF 12 Suspension may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Z-COF 12 Suspension:

Use Z-COF 12 Suspension as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Take Z-COF 12 Suspension by mouth with or without food.

Shake well before each use.

Take Z-COF 12 Suspension with a full glass of water (8 oz/240 mL).

Drink plenty of water while taking Z-COF 12 Suspension.

Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.

If you miss a dose of Z-COF 12 Suspension, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Z-COF 12 Suspension.

Important safety information:

Z-COF 12 Suspension may cause dizziness or drowsiness. These effects may be worse if you take it with alcohol or certain medicines. Use Z-COF 12 Suspension with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.

Do not take appetite suppressants while you are taking Z-COF 12 Suspension without checking with your doctor.

Z-COF 12 Suspension has pseudoephedrine and dextromethorphan in it. Before you start any new medicine, check the label to see if it has pseudoephedrine or dextromethorphan in it too. If it does or if you are not sure, check with your doctor or pharmacist.

Do NOT exceed the recommended dose or take Z-COF 12 Suspension for longer than prescribed without checking with your doctor.

If your symptoms do not improve within 7 days or if they become worse, check with your doctor.

Do not use Z-COF 12 Suspension for a cough with a lot of mucous. Do not use it for a long-term cough (eg, caused by asthma, emphysema, smoking). However, you may use it for these conditions if your doctor tells you to.

Z-COF 12 Suspension may interfere with certain lab tests. Be sure that your doctor and lab personnel know you are taking Z-COF 12 Suspension.

Tell your doctor or dentist that you take Z-COF 12 Suspension before you receive any medical or dental care, emergency care, or surgery.

Use Z-COF 12 Suspension with caution in the ELDERLY; they may be more sensitive to its effects.

Z-COF 12 Suspension should be used with extreme caution in CHILDREN younger than 2 years old; safety and effectiveness in these children have not been confirmed.

PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Z-COF 12 Suspension, contact your doctor. You will need to discuss the benefits and risks of using Z-COF 12 Suspension while you are pregnant. It is not known if Z-COF 12 Suspension is found in breast milk. Do not breast-feed while taking Z-COF 12 Suspension.

Possible side effects of Z-COF 12 Suspension:

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

Diarrhea; dizziness; drowsiness; excitability; headache; irritability; nausea; stomach upset; trouble sleeping.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); difficulty urinating; fast, slow, or irregular heartbeat; fever; hallucinations; seizures; severe or persistent dizziness, lightheadedness, or headache; tremor.

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

See also: Z-COF2 side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include blurred vision; confusion; hallucinations; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; unusually fast, slow, or irregular heartbeat; vomiting.

Proper storage of Z-COF 12 Suspension:

Store Z-COF 12 Suspension at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Z-COF 12 Suspension out of the reach of children and away from pets.

General information:

If you have any questions about Z-COF 12 Suspension, please talk with your doctor, pharmacist, or other health care provider.

Z-COF 12 Suspension is to be used only by the patient for whom it is prescribed. Do not share it with other people.

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

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

This information is a summary only. It does not contain all information about Z-COF 12 Suspension. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Z-COF 12 resources

Z-COF 12 Side Effects (in more detail)
Z-COF 12 Use in Pregnancy & Breastfeeding
Z-COF 12 Drug Interactions
Z-COF 12 Support Group
0 Reviews for Z-COF2 - Add your own review/rating

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Cough and Nasal Congestion