Trelstar

Generic Name: Triptorelin Pamoate
Class: Antineoplastic Agents
VA Class: AN500
Chemical Name: 6-d-Tryptophan luteinizing hormone-releasing factor (pig)
Molecular Formula: C₆₄H₈₂N₁₈O₁₃
CAS Number: 57773-63-4

Special Alerts:

[Posted 10/20/2010] ISSUE: Gonadotropin-Releasing Hormone (GnRH) agonists will have new safety information added to the Warnings and Precautions section of the drug labels. This new information warns about increased risk of diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving these medications for the treatment of prostate cancer.

BACKGROUND: GnRH agonists are approved to treat the symptoms (palliative treatment) of advanced prostate cancer. The benefits of GnRH agonist use for earlier stages of prostate cancer that have not spread (non-metastatic prostate cancer) have not been established. FDA’s notification to manufacturers of GnRH agonists to add this safety information is based on the Agency’s review of several published studies. Most of the studies reviewed by FDA reported small but statistically significant increased risks of diabetes and/or cardiovascular events in patients receiving GnRH agonists.

RECOMMENDATIONS: Healthcare professionals should evaluate patients for risk factors for these diseases and carefully weigh the benefits and risks of using GnRH agonists before determining appropriate treatment for prostate cancer. Patients who are receiving treatment with GnRH agonists should undergo periodic monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c). Healthcare professionals should also monitor patients for signs and symptoms suggestive of development of cardiovascular disease and manage according to current clinical practice. For more information visit the FDA website at: and .

[Posted 05/03/2010] FDA notified healthcare professionals and patients of FDA’s preliminary and ongoing review which suggests an increase in the risk of diabetes and certain cardiovascular diseases in men treated with GnRH agonists, drugs that suppress the production of testosterone, a hormone that is involved in the growth of prostate cancer.

Most of the studies reviewed by FDA reported small, but statistically significant increased risks of diabetes and/or cardiovascular events in patients receiving GnRH agonists. FDA’s review is ongoing and the agency has not made any conclusions about GnRH agonists and whether they increase the risk of diabetes and cardiovascular disease in patients receiving these medications for prostate cancer.

Healthcare professionals and patients should be aware of these potential safety issues and carefully weigh the benefits and risks of GnRH agonists when determining treatment choices. FDA recommends that patients receiving GnRH agonists should be monitored for development of diabetes and cardiovascular disease. Patients should not stop their treatment with GnRH agonists unless told to do so by their healthcare professional.

Some GnRH agonists are also used in women and in children for other indications than those above. There are no known comparable studies that have evaluated the risk of diabetes and heart disease in women and children taking GnRH agonists. For more information visit the FDA website at: and .

Introduction

Antineoplastic agent; synthetic decapeptide analog of gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone, gonadorelin);^{1 7} structurally related to leuprolide and goserelin.^{1 2 3 4 6 7}

Uses for Trelstar

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Prostate Cancer

Palliative treatment of advanced prostate cancer; considered alternative therapy when orchiectomy or estrogen therapy is not appropriate or is unacceptable to the patient.^{1 7}

Trelstar Dosage and Administration

Administration

IM Administration

Administer by IM injection once monthly (every 28 days) as a depot 1-month formulation or every 84 days (12 weeks) as a long-acting 3-month formulation.^{1 7}

Inject IM into buttock; rotate injection sites periodically.^{1 7}

Administer under the supervision of a qualified clinician.^{1 7}

Reconstitution

Reconstitute powder just prior to administration.^{1 7} Discard suspension if not used immediately after reconstitution.^{1 7}

Using a syringe with 20-gauge needle, add 2 mL of sterile water for injection to vial containing the powder (1- or 3-month formulation); do not reconstitute with other diluents.^{1 7} Shake well to disperse particles and obtain a uniform, milky suspension.^{1 7}

If using the single-dose delivery system, add contents of the prefilled syringe (2 mL of sterile water for injection) to vial containing the powder according to the manufacturer’s instructions.^{1 7} Mix well.^{1 7}

Withdraw entire contents of vial and use immediately.^{1 7}

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as triptorelin pamoate; dosage is expressed in terms of triptorelin.^{1 7}

Adults

Prostate Cancer

IM

3.75 mg every 28 days (monthly) as the 1-month formulation or 11.25 mg every 84 days (12 weeks) as the 3-month formulation.^{1 7}

Special Populations

Hepatic Impairment

Potential need for dosage adjustment not determined.¹

Renal Impairment

Potential need for dosage adjustment not determined.¹

Cautions for Trelstar

Contraindications

• 
  

  Known hypersensitivity to triptorelin or any other ingredient in the formulation, other GnRH agonists, or GnRH.^{1 7}

  
  


• 
  

  Known or suspected pregnancy.^{1 7}

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Endocrine Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Possible worsening of signs and/or symptoms of prostate cancer and/or development of new manifestations (e.g., bone pain, neuropathy, hematuria, urethral or bladder outlet obstruction) due to increases in serum testosterone concentrations during initial weeks of therapy.^{1 2 3 5 7}

Possible spinal cord compression contributing to paralysis; possibly fatal.^{1 2 5 7}

Increased risk of neurologic and/or genitourinary complications during initial therapy in patients with prostate cancer and metastatic vertebral lesions and/or urinary tract obstruction.^{1 7} Observe such patients closely during initial weeks of therapy.^{1 5 7}

If spinal cord compression or renal impairment develops, institute standard treatment of these complications; consider immediate orchiectomy in extreme cases.^{1 7}

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactic shock and angioedema reported rarely.^{1 7} If such reactions occur, discontinue immediately and provide supportive and symptomatic care.^{1 7}

Major Toxicities

Pituitary Apoplexy

Pituitary apoplexy, a clinical syndrome resulting from infarction of the pituitary gland, reported rarely.^{1 7} Most cases occur within 2 weeks of the first dose, sometimes within the first hour.^{1 7} If manifestations occur (e.g., sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, sometimes cardiovascular collapse), immediate medical attention required.^{1 7} In most cases, pituitary adenoma diagnosed.¹

General Precautions

Laboratory Monitoring

Periodically determine serum testosterone and prostate-specific antigen concentrations to monitor therapeutic response.^{1 7}

Specific Populations

Pregnancy

Category X.^{1 7} (See Contraindications under Cautions.)

Lactation

Not known whether distributed into milk; not recommended for use in nursing women.^{1 7}

Pediatric Use

Safety and efficacy not established in children.^{1 7}

Geriatric Use

Studies conducted principally in patients ≥65 years of age, since prostate cancer occurs mainly in an older patient population.^{1 7}

Common Adverse Effects

Temporary worsening of disease manifestations, hot flushes (flashes), skeletal pain, impotence, headache, pain at injection site, leg pain and edema, dysuria, hypertension.^{1 7}

Also observed with 3-month formulation: decreased hemoglobin and erythrocyte counts, increased BUN, increased serum concentrations of glucose, AST, ALT, and alkaline phosphatase.⁷

Interactions for Trelstar

Metabolism unlikely to involve CYP enzymes; effect of triptorelin on other drug-metabolizing enzymes unknown.⁷

Drugs That Induce Hyperprolactinemia

Potential pharmacologic interaction (possible decrease in triptorelin efficacy due to decreased number of GnRH receptors) with drugs such as antipsychotic agents, methyldopa, metoclopramide, and reserpine.^{1 6 7}

Trelstar Pharmacokinetics

Absorption

Bioavailability

Not active when administered orally.^{1 7}

Following IM administration as Trelstar Depot or Trelstar LA, peak plasma concentrations usually are attained within 1 or 3 hours, respectively.^{1 7}

Duration

Following IM injection of Trelstar Depot or Trelstar LA in males, therapeutic plasma concentrations persist for 1 or 3 months, respectively.^{1 7}

Distribution

Extent

Not known whether triptorelin is distributed into milk.^{1 7}

Plasma Protein Binding

No evidence that triptorelin binds to plasma proteins.^{1 7}

Elimination

Metabolism

Metabolism is unknown; involvement of CYP enzymes is unlikely.^{1 7} No metabolites identified to date.^{1 7}

Elimination Route

Hepatic and renal elimination.^{1 7}

Half-life

Approximately 3 hours.^{1 7}

Special Populations

In males with hepatic impairment or moderate or severe renal impairment, AUC increased 2- to 4-fold compared with healthy males.^{1 7}

Stability

Storage

Parenteral

Powder for Injection

20–25°C (may be exposed to 15–30°C).^{1 7} Do not freeze.⁷

Discard suspension if not used immediately after reconstitution.^{1 7}

ActionsActions

• 
  

  Potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses; greater activity than naturally occurring GnRH.^{1 7}

  
  


• 
  

  Transient surge in circulating levels of LH, FSH, testosterone, and estradiol observed after initial administration.^{1 7} Sustained decreases in LH and FSH secretion and reduced testicular and ovarian steroidogenesis observed following chronic, continuous administration (generally 2–4 weeks after initiation of therapy).^{1 4 7}

  
  


• 
  

  Reduction of serum testosterone in males comparable to effects achieved after surgical castration; results in inactivation of physiologic functions and tissues dependent on testosterone.^{1 2 4 7} These effects usually are reversible after cessation of therapy.^{1 7}

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Risk of worsening manifestations of prostate cancer during initial weeks of therapy.^{1 7}

  
  


• 
  

  Importance of promptly reporting weakness or paresthesia of lower limbs and/or worsening of urinary signs and symptoms to clinicians.⁶

  
  


• 
  

  Importance of promptly reporting sudden onset of headache, vomiting, or visual changes to clinicians.^{1 7}

  
  


• 
  

  Risk of anaphylactoid and other sensitivity reactions.^{1 7}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{1 7}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 7} If used during pregnancy, apprise of potential fetal hazard.⁷

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

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

Triptorelin Pamoate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IM use only	3.75 mg (of triptorelin)	Trelstar Depot	Watson
			Trelstar Depot Clip’n’Ject	Watson
		11.25 mg (of triptorelin)	Trelstar LA	Watson
			Trelstar LA Clip’n’Ject	Watson

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 November 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Watson Pharma. Trelstar Depot 3.75 mg (triptorelin pamoate for injectable suspension) prescribing information. Corona, CA; 2006 Aug.

2. Parmar H, Phillips RH, Lightman SL et al. Randomised controlled study of orchidectomy vs long-acting D-Trp-6-LHRH microcapsules in advanced prostatic carcinoma. Lancet. 1985; 2:1201-5. [PubMed 2866289]

3. Mahler C. Is disease flare a problem? Cancer. 1993; 72:3799-802.

4. Rolandi E, Martorana G, Franceschini R et al. Treatment of prostatic cancer with a depot preparation of an LHRH analogue: endocrine effects. Curr Ther Res. 1985; 38:670-5.

5. Kahan A, Delrieu F, Amor B et al. Disease flare induced by D-Trp⁶-LHRH analogue in patients with metastatic prostatic cancer. Lancet. 1984; 1:971-2. [IDIS 184509] [PubMed 6143912]

6. Pharmacia & Upjohn, Kalomazoo, MI: Personal communication.

7. Watson Pharma. Trelstar LA 11.25 mg (triptorelin pamoate for injectable suspension) prescribing information. Corona, CA: 2006 Aug.

8. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52.

More Trelstar resources

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

Compare Trelstar with other medications

• Prostate Cancer

Tequin Suspension

Generic Name: Gatifloxacin (ga-ti-FLOKS-a-sin)
Brand Name: Tequin

Tequin Suspension is used for:

Treating infections caused by certain bacteria.

Tequin Suspension is a fluoroquinolone antibiotic. It works by stopping the production of proteins that bacteria need to survive.

Do NOT use Tequin Suspension if:

• you are allergic to any ingredient in Tequin Suspension or to similar medicines (eg, ciprofloxacin)


• you have low blood potassium or diabetes


• you or a family member have a rare heart condition known as congenital prolongation of the QTc interval


• you are taking medicines for heart rhythm disturbances (eg, quinidine, procainamide, amiodarone, sotalol), cisapride, ketolides (eg, telithromycin), a macrolide antibiotic (eg, erythromycin), pimozide, or ziprasidone

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

Before using Tequin Suspension:

Some medical conditions may interact with Tequin Suspension. Tell your health care provider 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 heart problems, including a slow heartbeat, a history of lack of blood supply to your heart, or hardening of the arteries


• if you have a history of low blood potassium levels, diabetes, or kidney or liver problems


• if you have Alzheimer disease, tendonitis, or a history of seizures


• if you have a central nervous system disease or increased pressure in the head

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

• Antidepressants (eg, amitriptyline), antihistamines (eg, diphenhydramine, loratadine), arsenic, azole antifungals (eg, ketoconazole), certain medicines for heart rhythm disturbances (eg, quinidine, procainamide, amiodarone, sotalol), cisapride, diuretics (eg, hydrochlorothiazide, furosemide), droperidol, ketolides (eg, telithromycin, macrolide antibiotics (eg, erythromycin), phenothiazines (eg, chlorpromazine), pimozide , or ziprasidone because side effects, such as racing heartbeat, dizziness, fainting, life-threatening irregular heartbeat leading to unconsciousness, may be increased by Tequin Suspension


• Probenecid because the actions and side effects of Tequin Suspension may be increased


• Digoxin because the side effects may be increased by Tequin Suspension


• Anticoagulants (eg, warfarin) because side effects, including risk of bleeding, may be increased by Tequin Suspension


• Insulin, sulfonylureas (eg, glyburide), or other medicines for diabetes because the risk of blood sugar changes may be increased

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

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

• Tequin Suspension may be taken with or without food.


• Shake well before using.


• Tequin Suspension works best if it is taken at the same time each day.


• Tequin Suspension should be taken 4 hours before any other medicines or dietary supplements that contain aluminum, buffered didanosine, calcium, iron, magnesium, sucralfate, or zinc.


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


• To clear up your infection completely, continue using Tequin Suspension for the full course of treatment even if you feel better in a few days.


• Do not miss any doses of Tequin Suspension. If you miss a dose, 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 Tequin Suspension.

Important safety information:

• Tequin Suspension may cause dizziness, drowsiness, or changes in vision. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Tequin Suspension. Using Tequin Suspension alone, with certain other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks.


• Tequin Suspension is effective only against bacteria. It is not effective for treating viral infections (eg, the common cold).


• It is important to use Tequin Suspension for the full course of treatment. Failure to do so may decrease the effectiveness of Tequin Suspension and may increase the risk that the bacteria will no longer be sensitive to Tequin Suspension and will not be able to be treated by this or certain other antibiotics in the future.


• Long-term or repeated use of Tequin Suspension may cause a second infection. Your doctor may want to change your medicine to treat the second infection. Contact your doctor if signs of a second infection occur.


• If severe diarrhea, stomach pain/cramps or bloody stools occur, contact your doctor immediately. This could be a symptom of a serious side effect requiring immediate medical attention. Do not treat diarrhea without consulting your doctor.


• Tequin Suspension may cause increased sensitivity to the sun. Avoid exposure to the sun, sunlamps, or tanning booths until you know how you react to Tequin Suspension. Use a sunscreen or protective clothing if you must be outside for a prolonged period.


• Phenylketonuria patients - Tequin Suspension contains phenylalanine.


• Tequin Suspension may cause low blood sugar (eg, increased heartbeat, headache, chills, sweating, tremor, increased hunger, changes in vision, nervousness, weakness, dizziness, drowsiness, fainting) or high blood sugar (eg, thirst, increased urination, confusion, drowsiness, flushing, rapid breathing, fruity breath odor). If these symptoms occur, tell your doctor immediately.


• Use Tequin Suspension with caution in the ELDERLY because they may be more sensitive to its effects, especially blood sugar changes.


• Tequin Suspension is not recommended for use in CHILDREN younger than 18 years of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, discuss with your doctor the benefits and risks of using Tequin Suspension during pregnancy. It is unknown if Tequin Suspension is excreted in breast milk. If you are or will be breast-feeding while you are using Tequin Suspension, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Tequin 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; headache; mild diarrhea; nausea; stomachache; vaginal irritation; vomiting.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody stools; changes in mood or behavior; chest pain or pounding in the chest; confusion; convulsions; depression; excessive hunger, thirst, or urination; fainting; fast or irregular heartbeat; "fruity"-smelling breath; hallucinations; hoarseness; lightheadedness; loss of consciousness; nervousness; nightmares; pale skin; paranoia; restlessness; seizures; severe or continuous diarrhea; sleeplessness; stomach pain/cramps; sweating; tendon or joint pain or swelling; tremors; unusual or severe drowsiness or dizziness; vision changes.

This is not a complete list of all side effects that may occur. If you have questions or need medical advice about side effects, contact your doctor or health care provider. You may report side effects to the FDA at 1-800-FDA-1088 (1-800-332-1088) or at http://www.fda.gov/medwatch.

See also: Tequin 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 (http://www.aapcc.org/DNN/), or emergency room immediately.

Proper storage of Tequin Suspension:

Before mixing, store Tequin Suspension at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. After mixing, store the suspension in the tightly closed bottle in the refrigerator (36 to 46 degrees F; 2 to 8 degrees C) for up to 14 days. Keep Tequin Suspension out of the reach of children and away from pets.

General information:

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


• Tequin 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.

This information is a summary only. It does not contain all information about Tequin 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

Copyright © 2012 Wolters Kluwer Health, Inc.

More Tequin resources

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

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• Anthrax
• Anthrax Prophylaxis
• Bladder Infection
• Bronchitis
• Gonococcal Infection, Uncomplicated
• Kidney Infections
• Otitis Media
• Pneumonia
• Sinusitis
• Skin Infection
• Tuberculosis, Active
• Urinary Tract Infection

Idursulfase

Class: Enzymes
Chemical Name: α-L-iduronate sulfate sulfatase
Molecular Formula: C₂₆₈₉H₄₀₅₇N₆₉₉O₇₉₂S₁₄
CAS Number: 50936-59-9
Brands: Elaprase

• Risk of Anaphylaxis


• 
  

  Life-threatening anaphylactic reactions observed in some patients during idursulfase infusions. Appropriate medical support should be readily available.

  
  

• 
  

  Biphasic anaphylactic reactions also observed after administration. Patients who experienced anaphylactic reactions may require prolonged observation.

  
  


• 
  

  Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions; may require additional monitoring.

  
  

Introduction

Biosynthetic (recombinant DNA origin) form of human iduronate-2-sulfatase; lysosomal enzyme that catalyzes the hydrolysis of the 2-sulfate esters of terminal iduronate sulfate residues from the glycosaminoglycans dermatan sulfate and heparan sulfate.^{1 2 4 5 6 7}

Uses for Idursulfase

Hunter Syndrome

Management of Hunter syndrome (mucopolysaccharidosis II, MPS II);^{1 2 4 5 6} designated an orphan drug by FDA for use in this condition.³

Hunter syndrome is an X-linked recessive disease characterized by a deficiency of the lysosomal enzyme iduronate-2-sulfatase.^{1 2 4 4 5 6}

In patients with Hunter disease, reduced or absent iduronate-2-sulfatase activity results in progressive accumulation of glycosaminoglycans in the lysosomes of various cells, leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction.^{1 5 6}

Idursulfase improves endurance (measured by increases in walking distance) in patients with Hunter syndrome.^{1 2 4 5 6}

Idursulfase Dosage and Administration

Administration

Administer by IV infusion.¹

IV Administration

For solution compatibility and storage information, see Stability.

Administer by IV infusion using a 0.2-mcm filter.¹

Do not infuse idursulfase infusions simultaneously through the same IV line with other drugs.¹

Dilution

Prior to infusion, dilute the appropriate dose of commercially available idursulfase concentrated solution (2 mg of the drug per mL) in 100 mL of 0.9% sodium chloride for injection according to the manufacturer’s instructions.¹ Vials are for single use only; discard partially used vials of idursulfase solution.¹

Withdraw the calculated volume providing the appropriate dose of idursulfase from the appropriate number of vials and dilute in 100 mL of 0.9% sodium chloride injection.¹ Gently mix the solution in the infusion bag; do not shake.¹ Consult the manufacturer’s labeling for additional information on dilution and administration of idursulfase.¹

Rate of Administration

Administer by IV infusion at an initial infusion rate of 8 mL/hour for the first 15 minutes.¹ May increase infusion rate in increments of 8 mL/hour every 15 minutes in order to administer the entire volume within the desired time, up to a maximum rate of 100 mL/hour.¹ May administer the total volume of infusion in 1–3 hours; do not exceed 8 hours.¹ May decrease infusion rate, temporarily discontinue infusion, or stop the infusion for the particular visit if infusion-related reactions occur.¹

Dosage

The specific activity of idursulfase is 41–77 units/mg, with 1 unit defined as the amount of activity that results in the hydrolysis of 1 mcmol of heparin disaccharide substrate per hour under specified assay conditions.¹

Pediatric Patients

Hunter Syndrome

IV

Children ≥5 years of age: 0.5 mg/kg by IV infusion once weekly.¹

Adults

Hunter Syndrome

IV

0.5 mg/kg by IV infusion once weekly.¹

Prescribing Limits

Pediatric Patients

Hunter Syndrome

IV

Maximum infusion rate: 100 mL/hour.¹

Adults

Hunter Syndrome

IV

Maximum infusion rate: 100 mL/hour.¹

Special Populations

No special population dosage recommendations at this time.¹

Cautions for Idursulfase

Contraindications

• 
  

  The manufacturer states that there are no known contraindications to the use of idursulfase.¹

  
  

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Life-threatening hypersensitivity reactions (e.g., anaphylaxis, respiratory distress, hypoxia, hypotension, seizure, loss of consciousness, urticaria, angioedema of the throat and tongue) reported during and after idursulfase infusion in patients receiving the drug.^{1 5} Ensure that appropriate medical support measures are readily available during administration.¹

Consider prolonged observation in patients who experience initial severe or refractory reactions, since biphasic anaphylactic reactions occurring up to approximately 24 hours after treatment and recovery from an initial anaphylactic reaction have been reported.¹

Provide additional monitoring in patients with compromised respiratory function or acute respiratory disease, who may be at risk of serious acute exacerbation of their respiratory compromise secondary to infusion reactions.¹ Consider delaying idursulfase infusion in patients with concomitant acute respiratory and/or febrile illness.¹

If anaphylactic reactions or other severe allergic reaction occurs, immediately discontinue administration of the drug, and initiate appropriate medical treatment.¹ In clinical studies, treatment included hospitalization, epinephrine, inhaled β-adrenergic agonists, and corticosteroids.^{1 4 5} Consider resuming the infusion at a slower rate or discontinuing the idursulfase infusion for that visit.¹ May consider use of antihistamines and/or corticosteroids prior to and during subsequent infusions in patients who have experienced severe infusion reactions.^{1 4 5}

General Precautions

Antibody Formation

Possible formation of antibodies to idursulfase.^{1 2 4 6} Increased incidence of infusion reactions, including allergic reactions, reported in patients who developed IgG antibodies to idursulfase; in addition, decreased reduction of urinary glycosaminoglycan excretion reported in patients who developed antibodies to idursulfase.¹ The relationship between the development of antibodies to idursulfase and clinical efficacy outcome is not fully known.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether idursulfase is distributed into milk.¹ Use with caution.¹

Pediatric Use

Patients ≥5 years of age have received idursulfase in clinical trials.¹ Clinical response to idursulfase was similar in children, adolescents, and adults.¹ Safety and efficacy of idursulfase in pediatric patients <5 years of age have not been established.¹

Geriatric Use

No experience in patients ≥65 years of age; unknown whether geriatric patients respond differently than younger individuals.¹

Common Adverse Effects

Pyrexia,^{1 2} headache,^{1 2} arthralgia,¹ limb pain,¹ pruritus,^{1 2} hypertension,¹ malaise,¹ visual disturbance,¹ wheezing,¹ abscess,¹ chest wall musculoskeletal pain,^{1 2} musculoskeletal dysfunction,¹ urticaria, ¹ anxiety/irritability,^{1 2} atrial abnormality,¹ dyspepsia,^{1 2} infusion site edema, injury,¹ pruritic rash,^{1 2} skin disorder,¹ superficial injury.¹

In clinical studies, the most frequent serious adverse effects related to idursulfase were hypoxic episodes.¹ The most common infusion-related reactions were headache, fever, cutaneous reactions, and hypertension.^{1 5}

Interactions for Idursulfase

No formal drug interaction studies to date.¹

Idursulfase Pharmacokinetics

Absorption

Plasma Concentrations

AUC values increased in a greater than dose proportional manner following single 1-hour IV infusion of idursulfase dosages ranging from 0.15–1.5 mg/kg.¹

Distribution

Extent

Not known whether idursulfase is distributed into milk.¹

Elimination

Half-life

44–48 minutes.¹

Stability

Storage

Parenteral

Solution for IV Infusion

2–8°C; protect from light and do not shake or freeze.¹ Vials are for single use only; discard any unused product.¹

Administer diluted solution without delay; if not used immediately, diluted solution is stable at 2–8°C ≤48 hours.¹ If held at room temperature, administer diluted solution within 8 hours.¹

ActionsActions

• 
  

  Biosynthetic (recombinant DNA origin) form of human iduronate-2-sulfatase, a lysosomal enzyme that catalyzes the hydrolysis of the 2-sulfate esters of terminal iduronate sulfate residues from the glycosaminoglycans dermatan sulfate and heparan sulfate in the lysosomes of various cell types.^{1 2 4 5 6 7}

  
  


• 
  

  Provides an exogenous source of iduronate-2-sulfatase in patients with Hunter syndrome.¹

  
  


• 
  

  Binds to mannose-6-phosphate receptors on the cell surface via mannose-6-phosphate residues on the oligosaccharide chains of the idursulfase molecule, which is then internalized and transported into lysosomes.¹

  
  


• 
  

  Enzymatic activity of idursulfase, which results in catabolism of accumulated glycosaminoglycans, is dependent on the posttranslational modification of a specific cysteine to formylglycine.¹

  
  

Advice to Patients

• 
  

  Importance of encouraging patients to participate in the Hunter Outcome Survey (http://www.elaprase.com or 866-888-0660) to understand the variability and progression of the disease and to continue to monitor and evaluate long-term treatment effects of idursulfase.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

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

Idursulfase

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, concentrate, for IV infusion	6 mg	Elaprase	Shire

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 September 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Shire Human Genetic Therapies, Inc. Elaprase (idursulfase) solution for intravenous infusion prescribing information. Cambridge, MA; 2007 Oct.

2. Muenzer J, Wraith JE, Beck M et al. A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med. 2006; 8:465-73. [PubMed 16912578]

3. 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). Rockville, MD; 2007 Feb 26. From FDA website. Accessed 2007 Mar 13.

4. Muenzer J, Gucsavas-Calikoglu M, McCandless SE et al. A phase I/II clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome). Mol Genet Metab. 2007; 90:329-37. [PubMed 17185020]

5. Muenzer J, Beck M, Eng CM et al. Multidisciplinary management of Hunter syndrome. Pediatrics.2009; 124 (suppl e):1228-39.

6. Okuyama T, Tanaka A, Suzuki Y et al. Japan Elaprase treatment (JET) study: idursulfase enzyme replacement therapy in adult patients with attenuated Hunter syndrome (Mucopolysaccharidosis II, MPS II). Mol Genet Metab. 2010; 99:18-25. [PubMed 19773189]

7. Manara R, Rampazzo A, Cananzi M et al. Hunter syndrome in an 11-year old girl on enzyme replacement therapy with idursulfase: brain magnetic resonance imaging features and evolution.J inherit Metab Dis. 2010 Jan 6. (Epub ahead of print)

More Idursulfase resources

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

• Idursulfase MedFacts Consumer Leaflet (Wolters Kluwer)


• Idursulfase Professional Patient Advice (Wolters Kluwer)


• idursulfase Intravenous Advanced Consumer (Micromedex) - Includes Dosage Information


• Elaprase Prescribing Information (FDA)


• Elaprase Consumer Overview

Compare Idursulfase with other medications

• Mucopolysaccharidosis Type II

Cromolyn Nebulizer Solution

Pronunciation: KROE-moe-lin
Generic Name: Cromolyn
Brand Name: Intal

Cromolyn Nebulizer Solution is used for:

Preventing bronchial asthma and decreasing the severity of asthma attacks. It is not used to treat sudden asthma attacks. It may also be used to treat other conditions as determined by your doctor.

Cromolyn Nebulizer Solution is a mast cell stabilizer. It works by stabilizing mast cells and preventing them from releasing their irritating chemicals. Some forms of recurrent or chronic asthma are due to the release of irritating chemicals from mast cells located in the breathing tubes (bronchial tubes of the lung).

Do NOT use Cromolyn Nebulizer Solution if:

• you are allergic to any ingredient in Cromolyn Nebulizer Solution

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

Before using Cromolyn Nebulizer Solution:

Some medical conditions may interact with Cromolyn Nebulizer Solution. 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 liver or kidney problems

Some MEDICINES MAY INTERACT with Cromolyn Nebulizer Solution. However, no specific interactions with Cromolyn Nebulizer Solution are known at this time.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Cromolyn Nebulizer Solution 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 Cromolyn Nebulizer Solution:

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

• Cromolyn Nebulizer Solution is for inhalation only.


• This medication should be used in a power-driven nebulizer with an adequate airflow rate equipped with a suitable face mask or mouthpiece. Do not mix with other medicines in the nebulizer.


• Squeeze the contents of the ampule into the solution container in your nebulizer. Once the nebulizer has been assembled and contains cromolyn inhalation solution, hold the mask close to the face and switch on the device. Breathe through the mouth and out through the nose in a normal, relaxed manner. Nebulization should take 5 to 10 minutes.


• Any solution remaining in the nebulizer after treatment needs to be discarded.


• Continue to use Cromolyn Nebulizer Solution even if you feel well. Do not miss any doses.


• If you miss a dose of Cromolyn Nebulizer Solution, use 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 use 2 doses at once.

Ask your health care provider any questions you may have about how to use Cromolyn Nebulizer Solution.

Important safety information:

• Cromolyn Nebulizer Solution may cause drowsiness. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Cromolyn Nebulizer Solution.


• It may take up to 4 weeks for the benefits of this medication to be noticeable.


• Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are using Cromolyn Nebulizer Solution.


• Carry an identification card at all times that says you are taking Cromolyn Nebulizer Solution.


• Cromolyn Nebulizer Solution is not recommended for use in CHILDREN younger than 2 years of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you are pregnant or plan on becoming pregnant, discuss with your doctor the benefits and risks of using Cromolyn Nebulizer Solution during pregnancy. It is unknown if Cromolyn Nebulizer Solution is excreted in breast milk. If you are or will be breast-feeding, check with your doctor to discuss the benefits and risks to your baby.

Possible side effects of Cromolyn Nebulizer Solution:

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:

Bad taste; cough; drowsiness; hoarseness; nausea; sneezing; throat irritation; tightness in the lungs; wheezing.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); breathing problems; severe nasal congestion.

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

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Cromolyn Nebulizer Solution may be harmful if swallowed.

Proper storage of Cromolyn Nebulizer Solution:

Store at controlled room temperature between 68 and 77 degrees F (20 and 25 degrees C), away from heat, moisture, and light. Do not store in the bathroom. Do not use the solution if it is discolored or contains particles. Store ampules in foil pouch until ready for use. Keep Cromolyn Nebulizer Solution out of the reach of children and away from pets.

General information:

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


• Cromolyn Nebulizer Solution 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 Cromolyn Nebulizer Solution. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Cromolyn resources

• Cromolyn Use in Pregnancy & Breastfeeding
• Cromolyn Drug Interactions
• Cromolyn Support Group
• 6 Reviews for Cromolyn - Add your own review/rating

Compare Cromolyn with other medications

• Asthma, Maintenance
• Inflammatory Bowel Disease
• Systemic Mastocytosis

ticagrelor

Generic Name: ticagrelor (tye KA grel or)

Brand Names: Brilinta

What is ticagrelor?

Ticagrelor keeps the platelets in your blood from coagulating (clotting) to prevent unwanted blood clots that can occur with certain heart or blood vessel conditions.

Ticagrelor is used to lower your risk of having a stroke or serious heart problems after you have had a heart attack or severe chest pain (angina).

Ticagrelor may also be used for purposes not listed in this medication guide.

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

Ticagrelor keeps your blood from coagulating (clotting) to prevent unwanted blood clots that can occur with certain heart or blood vessel conditions. Because of this drug action, ticagrelor can make it easier for you to bleed, even from a minor injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.

You may also have bleeding on the inside of your body, such as in your stomach or intestines. Call your doctor at once if you have black or bloody stools, or if you cough up blood or vomit that looks like coffee grounds. These could be signs of bleeding in your digestive tract. While you are taking ticagrelor, do not take aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) without your doctor's advice. NSAIDs include ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Cataflam, Voltaren), indomethacin (Indocin), meloxicam (Mobic), and others.

Ticagrelor may cause you to bleed more easily, especially if you have: a history of bleeding problems, surgery or a medical emergency, a disease affecting the blood vessels in your brain, a history of stomach or intestinal bleeding, or if you are 65 or older.

Many drugs (including some over-the-counter medicines and herbal products) can interact with ticagrelor. It is very important to tell your doctor about all medicines you have recently used. Ask your doctor before taking any medicine for pain, arthritis, fever, or swelling. These medicines may affect blood clotting and may also increase your risk of stomach bleeding. Any doctor, dentist, surgeon, or other medical care provider who treats you should know that you are taking ticagrelor.

What should I discuss with my healthcare provider before taking ticagrelor?

You should not use this medication if you are allergic to ticagrelor, or if you have:

• 
  

  severe liver disease;

  
  


• 
  

  any active bleeding;

  
  


• 
  

  stomach ulcer or bleeding; or

  
  


• 
  

  a history of bleeding in the brain (such as from a head injury).

  
  

To make sure you can safely take ticagrelor, tell your doctor if you have any of these other conditions:

• 
  

  liver disease;

  
  


• 
  

  asthma, COPD (chronic obstructive pulmonary disorder) or other breathing problem;

  
  


• 
  

  a history of stomach ulcer or colon polyps;

  
  


• 
  

  a history of stroke; or

  
  


• 
  

  a history of bleeding or blood clotting disorder.

  
  

Ticagrelor may cause you to bleed more easily, especially if you have:

• 
  

  a recent surgery or bleeding injury;

  
  


• 
  

  a disease affecting the blood vessels in your brain;

  
  


• 
  

  a history of stroke;

  
  


• 
  

  a history of bleeding problems;

  
  


• 
  

  a history of stomach or intestinal bleeding; or

  
  


• 
  

  if you are 65 or older.

  
  

FDA pregnancy category C. It is not known whether ticagrelor will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether ticagrelor passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using ticagrelor.

How should I take ticagrelor?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Ticagrelor should be taken together with aspirin. Follow your doctor's instructions about how much aspirin you should take.

Ticagrelor can be taken with or without food. Take the medicine at the same time each day.

Because ticagrelor keeps your blood from coagulating (clotting) to prevent unwanted blood clots, this medicine can also make it easier for you to bleed, even from a minor injury. Contact your doctor or seek emergency medical attention if you have any bleeding that will not stop.

If you need surgery or dental work, tell the surgeon or dentist ahead of time that you are using ticagrelor. You may need to stop using the medicine for at least 5 days before having surgery, to prevent excessive bleeding. Follow your doctor's instructions and start taking ticagrelor again as soon as possible.

Do not stop taking ticagrelor without first talking to your doctor, even if you have signs of bleeding. Use ticagrelor regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely. Stopping ticagrelor may increase your risk of a heart attack or stroke. Store at room temperature away from moisture and heat.

See also: Ticagrelor dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose can cause excessive bleeding.

What should I avoid while taking ticagrelor?

While you are taking ticagrelor, do not take aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) without your doctor's advice. NSAIDs include ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Cataflam, Voltaren), indomethacin (Indocin), meloxicam (Mobic), and others.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Avoid drinking alcohol. It may increase your risk of bleeding in your stomach or intestines. Ask a doctor or pharmacist before using any cold, allergy, pain, or sleep medication. Aspirin (sometimes abbreviated as ASA) is contained in many combination medicines. Taking certain products together can cause you to get too much aspirin which can increase your risk of bleeding. Check the label to see if a medicine contains aspirin or ASA.

Ticagrelor side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

• 
  

  feeling light-headed or short of breath, even with mild exertion or while lying down;

  
  


• 
  

  nosebleed or other bleeding that will not stop;

  
  


• 
  

  bloody or tarry stools, blood in your urine;

  
  


• 
  

  coughing up blood or vomit that looks like coffee grounds;

  
  


• 
  

  chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;

  
  


• 
  

  sudden numbness or weakness, especially on one side of the body;

  
  


• 
  

  sudden severe headache, confusion, problems with vision, speech, or balance;

  
  


• 
  

  pale skin, weakness, fever, or jaundice (yellowing of the skin or eyes); or

  
  


• 
  

  easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin.

  
  

Less serious side effects may include:

• 
  

  headache, mild dizziness;

  
  


• 
  

  cough; or

  
  


• 
  

  nausea, diarrhea.

  
  

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

Ticagrelor Dosing Information

Usual Adult Dose for Acute Coronary Syndrome:

Initiate treatment with a 180 mg (two 90 mg tablets) loading dose given orally and continue treatment with 90 mg orally twice daily. After the initial loading dose of aspirin (usually 325 mg), use a daily maintenance dose of aspirin of 75 to 100 mg.

Maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor. Avoid maintenance doses of aspirin above 100 mg daily.

What other drugs will affect ticagrelor?

Tell your doctor about all other medicines you use, especially:

• 
  

  dexamethasone (Cortastat, Dexasone, Solurex, DexPak);

  
  


• 
  

  digoxin (Lanoxin);

  
  


• 
  

  nefazodone;

  
  


• 
  

  an antibiotic such as clarithromycin (Biaxin), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole), rifabutin (Mycobutin), rifampin (Rifadin, Rifater, Rifamate), or telithromycin (Ketek);

  
  


• 
  

  antifungal medicine such as itraconazole (Sporanox), ketoconazole (Nizoral), miconazole (Oravig), or voriconazole (Vfend);

  
  


• 
  

  a blood thinner such as warfarin (Coumadin, Jantoven);

  
  


• 
  

  cholesterol-lowering medications such as lovastatin (Mevacor, Altoprev, Advicor) or simvastatin (Zocor, Simcor, Vytorin);

  
  


• 
  

  heart or blood pressure medication such as nicardipine (Cardene) or quinidine (Quin-G);

  
  


• 
  

  HIV or AIDS medication such as atazanavir (Reyataz), delavirdine (Rescriptor), efavirenz (Sustiva, Atripla), etravirine (Intelence), indinavir (Crixivan), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir, Kaletra), or saquinavir (Invirase); or

  
  


• 
  

  seizure medication such as carbamazepine (Carbatrol, Equetro, Tegretol), felbamate (Felbatol), oxcarbazepine (Trileptal), phenobarbital (Solfoton), phenytoin (Dilantin), or primidone (Mysoline).

  
  

There may be other drugs that can interact with ticagrelor. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More ticagrelor resources

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

• ticagrelor Advanced Consumer (Micromedex) - Includes Dosage Information


• Ticagrelor Professional Patient Advice (Wolters Kluwer)


• Ticagrelor MedFacts Consumer Leaflet (Wolters Kluwer)


• Brilinta Consumer Overview

Compare ticagrelor with other medications

• Acute Coronary Syndrome

Where can I get more information?

• Your pharmacist can provide more information about ticagrelor.

See also: ticagrelor side effects (in more detail)

Tham

Generic Name: tromethamine (troe METH a meen)

Brand Names: Tham

What is Tham (tromethamine)?

Tromethamine affects the balance of water and electrolytes in the body.

Tromethamine is used to treat metabolic acidosis (an electrolyte imbalance). Metabolic acidosis can have many causes. It often occurs after heart bypass surgery or cardiac arrest.

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

What is the most important information I should know about Tham (tromethamine)?

You should not receive this medication if you have uremia (urea circulating in your blood), or if you are unable to urinate (such as due to kidney failure).

Before receiving tromethamine, tell your doctor if you are allergic to any drugs, or if you have asthma, kidney disease, or congestive heart failure.

Tell your caregivers right away if you have any swelling or rapid weight gain, shortness of breath, weak or shallow breathing, swelling or skin changes where the medicine was injected, fast heart rate, or feeling like you might pass out.

What should I discuss with my health care provider before receiving Tham (tromethamine)?

You should not receive this medication if you have uremia (urea circulating in your blood) or if you are unable to urinate (such as due to kidney failure).

If possible, before you receive tromethamine, tell your doctor if you are allergic to any drugs, or if you have:

• 
  

  kidney disease;

  
  


• 
  

  congestive heart failure; or

  
  


• 
  

  asthma or other breathing problems.

  
  

If you have any of these conditions, you may not be able to receive tromethamine, or you may need dosage adjustments or special tests during treatment.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether tromethamine passes into breast milk or if it could harm a nursing baby. Do not receive this medication without telling your doctor if you are breast-feeding a baby.

In an emergency situation, it may not be possible before you are treated with tromethamine to tell your caregivers about any health conditions you have or if you are pregnant or breast-feeding. However, make sure any doctor caring for your pregnancy or your baby knows that you have received this medication.

How is tromethamine given?

Tromethamine is given as an injection under the skin or into a muscle. You will receive this injection in a clinic or hospital setting. The medicine must be given slowly through an IV infusion.

Tromethamine is often given for only a short period of time, such as one day. The length of time you receive treatment will depend on how your body responds to the medication.

To be sure this medication is not causing harmful effects, your blood and heart function will need to be checked throughout your treatment.

After treatment with tromethamine, you will be closely watched and tested to make sure the medication has been effective and you no longer have any effects of metabolic acidosis.

What happens if I miss a dose?

Since tromethamine is usually given as needed in a hospital setting, it is not likely that you will miss a dose.

What happens if I overdose?

Seek emergency medical attention if you think you have received too much of this medicine.

Overdose symptoms may include fast heart rate, rapid weight gain, trouble breathing; confusion, sweating, or seizure (convulsions).

What should I avoid after receiving Tham (tromethamine)?

Follow your doctor's instructions about any restrictions on food, beverages, or activity after your treatment with tromethamine.

Tham (tromethamine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Tell your caregivers at once if you have any of these serious side effects:

• 
  

  swelling, rapid weight gain, feeling short of breath;

  
  


• 
  

  weak or shallow breathing;

  
  


• 
  

  pain, swelling, or skin changes where the medicine was injected;

  
  


• 
  

  fast heart rate; or

  
  


• 
  

  feeling like you might pass out.

  
  

Less serious side effects may include:

• 
  

  hunger, weakness;

  
  


• 
  

  confusion, irritability;

  
  


• 
  

  drowsiness, dizziness, tremors;

  
  


• 
  

  headache, weakness; or

  
  


• 
  

  increased sweating.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Tham (tromethamine)?

Before receiving tromethamine, tell your doctor if you have recently used any type of medication that can slow your breathing, such as a narcotic pain reliever.

This list is not complete and there may be other drugs that can interact with tromethamine. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Tham resources

• Tham Side Effects (in more detail)
• Tham Dosage
• Tham Drug Interactions
• Tham Support Group
• 0 Reviews for Tham - Add your own review/rating

• Tham Monograph (AHFS DI)


• Tham Prescribing Information (FDA)


• Tromethamine Professional Patient Advice (Wolters Kluwer)

Compare Tham with other medications

• Metabolic Acidosis

Where can I get more information?

• Your doctor or pharmacist can provide more information about tromethamine.

See also: Tham side effects (in more detail)

Bisoprolol 2.5mg / 5mg / 10mg film coated tablet

1. Name Of The Medicinal Product

Bisoprolol 2.5 mg film coated tablet

Bisoprolol 5 mg film coated tablet

Bisoprolol 10 mg film coated tablet

2. Qualitative And Quantitative Composition

For 2.5mg:

Each film-coated tablet contains 2.5 mg Bisoprolol fumarate.

For 5mg:

Each film-coated tablet contains 5 mg Bisoprolol fumarate

For 10mg:

Each film-coated tablet contains 10 mg Bisoprolol fumarate

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film-coated tablet

For 2.5mg:

White to off white, round, biconvex, film coated tablets, debossed 'b1' on one side and break line on other side

For 5mg:

White to off white, round, biconvex, film coated tablets, debossed 'b2' on one side and break line on other side

For 10mg:

White to off white, round, biconvex, film coated tablets, debossed 'b3' on one side and break line on other side

The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of Hypertension

Treatment of stable chronic angina

Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides (for additional information see section 5.1)

4.2 Posology And Method Of Administration

Administration:

For oral use.

Bisoprolol fumarate tablet should be taken in morning and can be taken with food in morning. They should be swallowed in liquid and should not be chewed.

Treatment of hypertension and chronic stable angina pectoris

Adults

The dosage should be individually adjusted. It is recommended to start with 5 mg per day. The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg per day.

Patients with renal impairment

In patients with severe renal impairment (creatinine clearance < 20 ml/min) the dose should not exceed 10 mg once daily. This dosage may eventually be divided into halves.

Patients with severe liver impairment

No dosage adjustment is required, however careful monitoring is advised.

Elderly

No dosage adjustment is normally required. It is recommended to start with the lowest possible dose.

Children

There is no experience with bisoprolol in children, therefore its use cannot be recommended for children.

Discontinuation of treatment

Treatment should not be stopped abruptly (see section 4.4). The dosage should be diminished slowly by a weekly halving of the dose.

Treatment of stable chronic heart failure

Adults

Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a beta-blocker, diuretics, and when appropriate cardiac glycosides. Patients should be stable (without acute failure) when bisoprolol treatment is initiated.

It is recommended that the treating physician should be experienced in the management of chronic heart failure.

Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration period and thereafter.

Titration phase

The treatment of stable chronic heart failure with bisoprolol requires a titration phase

The treatment with bisoprolol is to be started with a gradual uptitration according to the following steps:

- 1.25 mg once daily for 1 week, if well tolerated increase to

- 2.5 mg once daily for a further week, if well tolerated increase to

- 3.75 mg once daily for a further week, if well tolerated increase to

- 5 mg once daily for the 4 following weeks, if well tolerated increase to

- 7.5 mg once daily for the 4 following weeks, if well tolerated increase to

- 10 mg once daily for the maintenance therapy.

The maximum recommended dose is 10 mg once daily.

Close monitoring of vital signs (heart rate, blood pressure) and symptoms of worsening heart failure is recommended during the titration phase. Symptoms may already occur within the first day after initiating the therapy.

Treatment modification

If the maximum recommended dose is not well tolerated, gradual dose reduction may be considered.

In case of transient worsening of heart failure, hypotension, or bradycardia reconsideration of the dosage of the concomitant medication is recommended. It may also be necessary to temporarily lower the dose of bisoprolol or to consider discontinuation.

The reintroduction and/or uptitration of bisoprolol should always be considered when the patient becomes stable again.

If discontinuation is considered, gradual dose decrease is recommended, since abrupt withdrawal may lead to acute deterioration of the patients condition.

Treatment of stable chronic heart failure with bisoprolol is generally a long-term treatment.

Special population

Renal or hepatic impairment

There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired hepatic or renal function. Uptitration of the dose in these populations should therefore be made with additional caution.

Elderly

No dosage adjustment is normally required.

Children`

There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for children.

4.3 Contraindications

Bisoprolol is contraindicated in chronic heart failure patients with:

- acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy

- cardiogenic shock

- second or third degree AV block (without a pacemaker)

- sick sinus syndrome

- sinoatrial block

- Symptomatic bradycardia

- Symptomatic hypotension

- severe bronchial asthma or severe chronic obstructive pulmonary disease

- late stages of peripheral arterial occlusive disease and Raynaud's syndrome

- untreated phaeochromocytoma (see section 4.4)

- metabolic acidosis

- hypersensitivity to bisoprolol or to any of the excipients (See section 6.1)

4.4 Special Warnings And Precautions For Use

Special warnings:

Applies only to chronic heart failure:

The treatment of stable chronic heart failure with bisoprolol has to be initiated with special titration phase (see section 4.2).

Applies to all indications:

Especially in patients with ischemic heart disease the cessation of therapy with bisoprolol must not be done abruptly unless clearly indicated, because this may lad to transition worsening of heart condition (See section 4.2).

Precautions:

Applies only to hypertension or angina pectoris:

Bisoprolol must be used with caution in patients with hypertension or angina pectoris and accompanying heart failure.

Applies only to chronic heart failure:

The initiation of treatment with bisoprolol necessitates regular monitoring. For posology and method of administration please (See section 4.2).

There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the following diseases and conditions:

- insulin dependent diabetes mellitus (type I)

- severely impaired renal function

- severely impaired hepatic function

- restrictive cardiomyopathy

- congenital heart disease

- haemodynamically significant organic valvular disease

- myocardial infarction within 3 months

Applies to all indications:

Bisoprolol must be used with caution in:

- bronchospasm (bronchial asthma, obstructive airways diseases).

In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, bronchodilating therapy is recommended to be given concomitantly. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of beta2-stimulants may have to be increased.

- diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia (e.g. tachycardia, palpitations or sweating) can be masked.

- strict fasting

- ongoing desensitisation therapy

As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic effect.

- first degree AV block

- Prinzmetal's angina

- peripheral arterial occlusive disease (intensification of complaints might happen especially during the start of therapy)

- general anaesthesia

In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance beta-blockade be continued peri-operatively. The anaesthesist must be aware of beta-blockade because of the potential for interactions with other drugs, resulting in bradyarrhythmias, attenuation of the reflex tachycardia and the decreased reflex ability to compensate for blood loss. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.

Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after carefully balancing the benefits against the risks.

In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-receptor blockade.

Under treatment with bisoprolol the symptoms of a thyreotoxicosis may be masked.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Combinations not recommended

Applies only to chronic hart failure:

• Class I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Applies to all indications:

• Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type: Negative influence on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on β-blocker treatment may lead to profound hypotension and atrioventricular block.

• Centrally acting antihypertensive drugs such as clonidine and others (e.g. methyldopa, moxonodine, rilmenidine): Concomitant use of centrally acting antihypertensive drugs may worsen heart failure by a decrease in the central sympathetic tonus (reduction of heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase risk of “rebound hypertension”.

Combinations to be used with caution

Applies only to hypertension or angina pectoris:

Class-I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Applies to all indications

• Calcium antagonists of the dihydropyridine type such as felodipine and amlodipine: Concomitant use may increase the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with heart failure cannot be excluded.

• Class-III antiarrhythmic drugs (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated.

• Topical beta-blockers (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol.

• Parasympathomimetic drugs: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.

• Insulin and oral antidiabetic drugs: Increase of blood sugar lowering effect. Blockade of beta-adrenoreceptors may mask symptoms of hypoglycaemia.

• Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension (for further information on general anaesthesia see also section 4.4.).

• Digitalis glycosides: Reduction of heart rate, increase of atrio-ventricular conduction time.

• Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol.

• β-Sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents.

• Sympathomimetics that activate both β- and α-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with bisoprolol may unmask the α-adrenoceptor-mediated vasoconstrictor effects of these agents leading to blood pressure increase and exacerbated intermittent claudication. Such interactions are considered to be more likely with nonselective β-blockers.

• Concomitant use with antihypertensive agents as well as with other drugs with blood pressure lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of hypotension.

Combinations to be considered

• Mefloquine: increased risk of bradycardia

• Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blockers but also risk for hypertensive crisis.

• Rifampicin: Slight reduction of the half-life of bisoprolol due to the induction of hepatic drugmetabolising enzymes. Normally no dosage adjustment is necessary.

• Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances.

4.6 Pregnancy And Lactation

Pregnancy:

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general, beta-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and newborn infant. If treatment with beta-adrenoceptor blockers is necessary, beta1-selective adrenoceptor blockers are preferable.

Bisoprolol is not recommended during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplacental blood flow and the fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus alternative treatment should be reccomended. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.

Lactation:

There are no data on the excretion of bisoprolol excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.

4.7 Effects On Ability To Drive And Use Machines

In a study with coronary heart disease patients bisoprolol did not impair driving performance. However, due to individual variations in reactions to the drug, the ability to drive a vehicle or to operate machinery may be impaired. This should be considered particularly at start of treatment and upon change of medication as well as in conjunction with alcohol.

4.8 Undesirable Effects

The following definitions apply to the frequency terminology used hereafter:

Very common (

Common (

Uncommon (

Rare (

Very rare (< 1/10,000)

Psychiatric disorders:

Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

Nervous system disorders:

Common: dizziness*, headache*

Rare: syncope

Eye disorders:

Rare: reduced tear flow (to be considered if the patient uses lenses).

Very rare: conjunctivitis.

Ear and labyrinth disorders:

Rare: hearing disorders.

Cardiac disorders:

Very common: bradycardia (in patients with chronic heart failure).

Common: worsening of pre-existing heart failure (in patients with chronic heart failure).

Uncommon: AV-conduction disturbances, worsening of pre-existing heart failure (in patients with hypertension or angina pectoris); bradycardia (in patients with hypertension or angina pectoris).

Vascular disorders:

Common: feeling of coldness or numbness in the extremities, hypotension especially in patient with heart failure.

Respiratory, thoracic and mediastinal disorders:

Uncommon: bronchospasm in patients with bronchial asthma or a history of obstructive airways disease.

Rare: allergic rhinitis.

Gastrointestinal disorders:

Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.

Hepatobiliary disorders:

Rare: hepatitis.

Skin and subcutaneous tissue disorders:

Rare: hypersensitivity reactions (such as itching, flush, rash).

Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.

Musculoskeletal and connective tissue disorders:

Uncommon: muscular weakness and cramps.

Reproductive system and breast disorders:

Rare: potency disorders

General disorders:

Common: asthenia (in patients with chronic heart failure), fatigue*.

Uncommon: asthenia (in patients with hypertension or angina pectoris)

Investigations:

Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT).

Applies only to hypertension or angina pectoris:

*These symptoms especially occur at the beginning of the therapy. They are generally mild and usually disappear within 1 - 2 weeks.

4.9 Overdose

The most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is limited experience with overdose of bisoprolol, only a few cases of overdose with bisoprolol have been reported. Bradycardia and/or hypotension were noted. All patients recovered. There is a wide inter-individual variation in sensitivity to one single high dose of bisoprolol and patients with heart failure are probably very sensitive.

In general, if overdose occurs, discontinuation of bisoprolol treatment and supportive and symptomatic treatment is recommended.

Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures may be considered when clinically warranted.

Bradycardia: Administer intravenous atropine. If the response is inadequate, isoprenaline or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.

Hypotension: Intravenous fluids and vasopressors should be administered. Intravenous glucagon may be useful.

AV block (second or third degree): Patients should be carefully monitored and treated with isoprenaline infusion or temporary pacing..

Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as isoprenaline, beta2-sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

Limited data suggest that bisoprolol is hardly dialysable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Beta blocking agents, selective

ATC Code: C07AB07

Bisoprolol is a potent highly beta₁-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and without relevant membrane stabilising activity. It only shows low affinity to the beta₂-receptor of the smooth muscles of bronchi and vessels as well as to the beta₂-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta₂-mediated metabolic effects. Its beta₁-selectivity extends beyond the therapeutic dose range.

Chronic heart failure:

In total 2647 patients were included in the CIBIS II trial. 83% (n = 2202) were in NYHA class III and 17% (n = 445) were in NYHA class IV. They had stable symptomatic systolic heart failure (ejection fraction <35%, based on echocardiography). Total mortality was reduced from 17.3% to 11.8% (relative reduction 34%). A decrease in sudden death (3.6% vs 6.3%, relative reduction 44%) and a reduced number of heart failure episodes requiring hospital admission (12% vs 17.6%, relative reduction 36%) was observed. Finally, a significant improvement of the functional status according to NYHA classification has been shown. During the initiation and titration of bisoprolol hospital admission due to bradycardia (0.53%), hypotension (0.23%), and acute decompensation (4.97%) were observed, but they were not more frequent than in the placebo-group (0%, 0.3% and 6.74%). The numbers of fatal and disabling strokes during the total study period were 20 in the bisoprolol group and 15 in the placebo group.

The CIBIS III trial investigated 1010 patients aged

There was a trend toward higher frequency of chronic heart failure worsening when bisoprolol was used as the initial 6 months treatment. Non inferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, although the two strategies for initiation of CHF treatment showed a similar rate of the primary combined endpoint death and hospitalization at study end (32.4% in the bisoprolol-first group vs. 33.1 % in the enalapril-first group, per-protocol population). The study shows that bisoprolol can also be used in elderly chronic heart failure patients with mild to moderate disease.

Hypertension or angina pectoris:

Bisoprolol is used for the treatment of hypertension and angina pectoris. As with other Beta- 1-blocking agents, the method of acting in hypertension is unclear. However, it is known that Bisoprolol reduces plasma renin activity markedly.

Antianginal mechanism: Bisoprolol by inhibiting the cardiac beta receptors inhibits the response given to sympathetic activation. That results in the decrease of heart rate and contractility this way decreasing the oxygen demand of the cardiac muscle.

In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated peripheral resistance decreases.

5.2 Pharmacokinetic Properties

Bisoprolol is absorbed almost completely from the gastrointestinal tract. Together with the very small first pass effect in the liver, this results in a high bioavailability of approximately 90%. The plasma protein binding of bisoprolol is about 30 %. The distribution volume is 3.5 l/kg. The total clearance is approximately 15 l/h.

The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage.

Bisoprolol is excreted from the body by two routes, 50 % is metabolised by the liver to inactive metabolites which are then excreted by the kidneys. The remaining 50 % is excreted by the kidneys in an unmetabolised form. Since elimination takes place in the kidneys and the liver to the same extent a dosage adjustment is not required for patients with impaired liver function or renal insufficiency.

In patients with chronic heart failure (NYHA stage III) the plasma levels of bisoprolol are higher and the half life is prolonged compared to healthy volunteers. Maximum plasma concentration at steady state is 64±21 ng/ml at a daily dose of 10 mg and the half life is 17±5 hours.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity..

Like other beta-blockers, bisoprolol caused maternal (decreased food intake and decreased body weight) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) at high doses but was not teratogenic.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core Tablet:

Cellulose microcrystalline

Sodium starch glycolate(Type-A)

Povidone K-30

Silica colloidal anhydrous

Magnesium stearate (E572)

Coating:

Hypromellose E-15 (E464)

Macrogol 400 (E553)

Titanium dioxide (E171)

Talc

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

18 months

6.4 Special Precautions For Storage

Do not store above 30°C

6.5 Nature And Contents Of Container

PVC/PVDC-Alu Blister or ALU-ALU Blister in Pack sizes of 20, 28, 30, 50, 56, 60, 90 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Accord Healthcare Ltd

Sage House 319, Pinner Road

North Harrow, Middlesex

HA1 4HF

United Kingdom

8. Marketing Authorisation Number(S)

Bisoprolol 2.5 mg film coated tablet: PL 20075/0316

Bisoprolol 5 mg film coated tablet: PL 20075/0317

Bisoprolol 10 mg film coated tablet: PL 20075/0318

9. Date Of First Authorisation/Renewal Of The Authorisation

21/12/2011

10. Date Of Revision Of The Text

21/12/2011