Alvimopan

Class: GI Drugs, Miscellaneous
Chemical Name: [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R), 4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate
Molecular Formula: C₂₅H₃₂N₂O₄ • 2H₂O
CAS Number: 170098-38-1
Brands: Entereg

• 
  

  Only for short-term (15 doses) use in hospitalized patients. (See MI under Cautions.)^{1 2}

  
  


• 
  

  For use only by hospitals enrolled in the Entereg Access Support and Education (EASE) program. (See Restricted Distribution Program under Dosage and Administration.)^{1 2}

  
  

REMS:

FDA approved a REMS for alvimopan to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of alvimopan and consists of the following: elements to assure safe use, communication plan, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Peripherally acting μ-opiate receptor antagonist.^{1 5 7 9 10 11 12 15 16}

Uses for Alvimopan

Postoperative Ileus

Acceleration of upper and lower GI recovery following partial large or small bowel resection with primary anastomosis.^{1 2 3 9 10 11 12 19}

Efficacy for management of postoperative ileus in women undergoing total abdominal hysterectomy† under general anesthesia not established to date.^{1 8}

Alvimopan Dosage and Administration

General

Restricted Distribution Program

• 
  

  Available only to hospitals for short-term inpatient use through a restricted distribution program (Entereg Access Support and Education [EASE] program) because of an increased risk of ischemic cardiovascular events associated with long-term therapy.^{1 2 4} (See MI under Cautions.)

  
  


• 
  

  To enroll in the EASE program, hospitals must perform bowel resection surgeries and confirm that staff who prescribe, dispense, or administer alvimopan are provided with the EASE program enrollment kit.^{1 2} Hospitals must have systems, order sets, protocols, or other measures in place to limit use to short-term (≤15 doses) therapy in inpatients.^{2 3} Hospitals must ensure alvimopan is not dispensed for outpatient use and the drug is not transferred to a nonregistered hospital.^{1 2}

  
  


• 
  

  Information about the EASE program is available at 866-423-6567 (866-4ADOLOR) or at .^{1 2} A database of registered hospitals is available on the website.²

  
  

Administration

Oral Administration

Preoperative dose administered in fasting patients in clinical studies; postoperative doses administered without regard to meals in studies.¹

Dosage

Available as alvimopan dihydrate; dosage expressed in terms of anhydrous alvimopan.¹

Adults

Postoperative Ileus

Oral

12 mg administered 0.5–5 hours prior to surgery followed by 12 mg twice daily beginning the day after surgery for a maximum of 7 days or until discharge.¹

Administer no more than 15 doses.^{1 2 3}

Prescribing Limits

Adults

Postoperative Ileus

Oral

Maximum of 15 doses over 7 days postoperatively in hospitalized patients.¹

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).^{1 15} Not recommended in severe hepatic impairment.^{1 15} (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required in patients with mild to severe renal impairment.^{1 15} Not recommended in patients with end-stage renal disease.¹ (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustment based on age not needed.¹

Crohn's Disease

No dosage adjustment required.^{1 8} (See Special Populations under Pharmacokinetics.)

Cautions for Alvimopan

Contraindications

• 
  

  Therapeutic doses of opiates for >7 consecutive days immediately prior to alvimopan administration.^{1 2}

  
  

Warnings/Precautions

Restricted Distribution Program

Only for short-term (15 doses) use in hospitalized patients.^{1 2} For use only by hospitals enrolled in the EASE program.^{1 2} (See Restricted Distribution Program under Dosage and Administration.)

MI

May be associated with increased incidence of MI when used long term;^{1 2 3 4 7} not found with short-term (i.e., ≤7 days) use following bowel resection.^{1 3 4} Causal relationship not established.¹ (See Boxed Warning and see Restricted Distribution Program under Dosage and Administration.)

Recent Opiate Use

Increased sensitivity to alvimopan possible with recent exposure to opiates; manifests principally as GI symptoms (e.g., abdominal pain, nausea, vomiting, diarrhea).¹ Use caution in patients who have received >3 doses of an opiate within 1 week prior to surgery.¹ (See Contraindications under Cautions.)

Bowel Obstruction

Not recommended for use in patients undergoing surgical correction of complete bowel obstruction.¹

Specific Populations

Pregnancy

Category B.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use caution.¹

Pediatric Use

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

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.^{1 15}

Hepatic Impairment

Slight increase in plasma alvimopan concentrations possible in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).¹ Monitor for adverse effects (e.g., diarrhea, abdominal pain or cramping) that may indicate alvimopan or metabolite accumulation; discontinue if such effects occur.^{1 15} (See Hepatic Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Use not recommended in patients with severe hepatic impairment (Child-Pugh class C).^{1 8 15} Substantially increased plasma concentrations possible.¹

Renal Impairment

Monitor for possible adverse effects in patients with renal impairment.^{1 15} Closely monitor those with severe renal impairment for adverse effects (e.g., diarrhea, abdominal pain or cramping) that may indicate elevated alvimopan or metabolite concentrations; discontinue if such effects occur.^{1 15} (See Renal Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Not studied in patients with end-stage renal disease.¹ Use not recommended.¹

Common Adverse Effects

Constipation,¹ hypokalemia,^{1 11} flatulence,¹ dyspepsia,¹ anemia,¹ back pain,¹ urinary retention.¹

Interactions for Alvimopan

Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 3A4, 2D6, or 2E1 or induce isoenzymes 1A2, 2B6, 2C9, 2C19, or 3A4.^{1 15}

Alvimopan does not inhibit P-glycoprotein; alvimopan and its metabolite are substrates for P-glycoprotein.^{1 15}

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.^{1 15}

Drugs Affecting or Affected by P-glycoprotein Transport

Pharmacokinetic interactions unlikely with mild-to-moderate P-glycoprotein inhibitors.^{1 15} The effect of potent P-glycoprotein inhibitors is unknown.^{1 15}

Pharmacokinetic interactions with P-glycoprotein substrates are unlikely.^{1 15}

Specific Drugs

Drug	Interaction	Comments
Antibiotics (preoperative oral antibiotics)	Decreased plasma concentrations of alvimopan metabolite; no alteration in alvimopan pharmacokinetics1	No dosage adjustment necessary1
Histamine H2-receptor antagonists	Decreased plasma concentrations of alvimopan metabolite; no alteration in alvimopan pharmacokinetics1 8	No dosage adjustment necessary1
Morphine	Pharmacokinetic interaction unlikely (no change in morphine pharmacokinetics);1 8 15 alvimopan does not reverse analgesic effects1	No dosage adjustment necessary1 8 15
Proton-pump inhibitors	Decreased plasma concentrations of alvimopan metabolite; no alteration in alvimopan pharmacokinetics1 8	No dosage adjustment necessary1

Alvimopan Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability averages 6% (range 1–19%).^{1 7 11}

Food

High-fat meal decreases rate and extent of absorption.¹

Distribution

Extent

Does not readily cross blood-brain barrier.^{1 6 7 14 15 16}

Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

Alvimopan: 80%.¹ Metabolite: 94%.¹ Bound to albumin.¹

Elimination

Metabolism

Metabolized by intestinal flora to active metabolite;¹ metabolite not required for pharmacologic activity.^{8 16}

No substantial hepatic metabolism.¹

Elimination Route

Excreted principally via biliary secretion (65%) and in the urine (35%).^{1 16}

Half-life

10–17 hours.¹

Special Populations

Exposure to alvimopan is 1.5-fold to twofold higher in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); accumulation possible after multiple doses.¹ Exposure may be increased approximately tenfold in patients with severe hepatic impairment (Child-Pugh class C).¹

Exposure to metabolite is twofold to fivefold higher in patients with moderate or severe renal impairment.¹ Alvimopan half-life is prolonged in patients with severe renal impairment.¹ Accumulation of alvimopan and metabolite is possible after multiple doses in patients with severe renal impairment.¹ Not studied in patients with end-stage renal disease.¹

Exposure to alvimopan is twofold higher in patients with quiescent Crohn’s disease relative to healthy individuals or those with active Crohn’s disease; metabolite concentrations are lower in patients with Crohn’s disease.¹

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).¹

Actions

• 
  

  Peripherally acting μ-opiate receptor antagonist.^{1 5 7 9 10 11 12 15 16}

  
  


• 
  

  Blocks μ-opiate receptors in GI tract, thereby antagonizing peripheral inhibitory effects of opiates on GI motility and improving GI function.^{1 7 14 16}

  
  


• 
  

  Does not readily cross the blood-brain barrier; therefore, does not affect opiate analgesic activity or precipitate opiate withdrawal, unlike centrally active opiate antagonists (e.g., naltrexone, naloxone).^{1 6 7 14 15 16}

  
  


• 
  

  Exhibits greater affinity for μ-opiate receptors than for δ- and κ-opiate receptors;^{7 14 15 16} a more potent μ-opiate receptor antagonist than naloxone.^{14 15}

  
  


• 
  

  Does not possess opiate agonist activity ¹ or affinity for nonopiate receptors, including α₁-, α₂-, and β-adrenergic; dopamine types 1 and 2 (D₁, D₂); serotonin type 2 (5-hydroxytryptamine [5-HT_2A]); histamine (H₁); GABA; benzodiazepine; and muscarinic receptors.^{15 16}

  
  

Advice to Patients

• 
  

  Importance of informing clinicians of long-term or intermittent opiate therapy, including any use of opiates in the week prior to receiving alvimopan.¹ Potential for alvimopan to precipitate GI symptoms (e.g., abdominal pain, nausea, vomiting, diarrhea) in patients who have recently received opiate therapy; importance of informing clinician if such adverse events occur.¹

  
  


• 
  

  Importance of informing patients that alvimopan is indicated for hospital use only and for no more than 7 days following bowel resection.¹

  
  


• 
  

  Advise patients that the most common adverse effects of alvimopan are constipation, dyspepsia, and flatulence.¹

  
  


• 
  

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

  
  


• 
  

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

Distribution of alvimopan is restricted.^{1 2} (See Restricted Distribution Program under Dosage and Administration.)

Alvimopan

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	12 mg (of anhydrous alvimopan)	Entereg	Adolor, (comarketed by GlaxoSmithKline)

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 October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

1. Adolor Corporation. Entereg (alvimopan) capsules prescribing information. Exton, PA; 2008 May.

2. Adolor Corporation. The EASE program. From Entereg website: (). Accessed 2008 Aug 28.

3. Food and Drug Administration. FDA News: FDA approves Entereg to help restore bowel function following surgery. Rockville, MD; 2008 May 20. From FDA website: .

4. Food and Drug Administration, Center for Drug Evaluation and Research. Application number 21-775: Risk assessment and risk mitigation review(s): Entereg (alvimopan). 2008 May 2. From FDA website: .

5. Maron DJ, Fry RD. New therapies in the treatment of postoperative ileus after gastrointestinal surgery. Am J Ther. 2008; 15:59-65. [PubMed 18223355]

6. McNicol ED, Boyce D, Schumann R et al. Mu-opioid antagonists for opioid-induced bowel dysfunction. Cochrane Database Syst Rev. 2008; 2:CD006332. [PubMed 18425947]

7. Kraft MD. Emerging pharmacologic options for treating postoperative ileus. Am J Health-Syst Pharm. 2007; 64 (Suppl 13):S13-20. [PubMed 17909271]

8. GlaxoSmithKline, Research Triangle Park, NC: Personal communication.

9. Büchler MW, Seiler CM, Monson JRT et al. Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study. Aliment Pharmacol Ther. 2008; 28:312-25.

10. Delaney CP, Weese JL, Hyman NH et al. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum. 2005; 48:1114-1129. [PubMed 15906123]

11. Viscusi ER, Goldstein S, Witkowski T et al. Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery. Surg Endosc. 2006; 20:64-70. [PubMed 16333556]

12. Wolff BG, Michelassi F, Gerkin TM et al. Alvimopan, a novel, peripherally acting opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg. 2004; 240:728-735. [PubMed 15383800]

13. Steinbrook RA. An opioid antagonist for postoperative ileus. N Engl J Med. 2001; 345:988-9. [PubMed 11575292]

14. Schmidt WK. Alvimopan (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg. 2001; 182 (Suppl 5A):27S-38S. [PubMed 11755894]

15. Leslie JB. Alvimopan for the management of postoperative ileus. Ann Pharmacother. 2005; 39:1502-10. [PubMed 16076918]

16. Leslie JB. Alvimopan: a peripherally acting mu-opioid receptor antagonist. Drugs Today. 2007; 43:611-625. [PubMed 17940638]

17. Reichle FM, Conzen PF. Methylnaltrexone, a new peripheral μ-receptor antagonist for the prevention and treatment of opioid-induced extracerebral side effects. Curr Opin Investig Drugs. 2008; 9:90-100. [PubMed 18183536]

18. Beattie DT, Cheruvu M, Mai N et al. The in vitro pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, ADL 08-0011 and methylnaltrexone. Naunyn Schmiedebergs Arch Pharmacol. 2007; 375:205-20. [PubMed 17340127]

19. Ludwig K, Enker WE, Delaney CP et al. Gastrointestinal tract recovery in patients undergoing bowel resection: resluts of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway. Arch Surg. 2008; 43:1098-1105.

More Alvimopan resources

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

• Alvimopan MedFacts Consumer Leaflet (Wolters Kluwer)


• Alvimopan Professional Patient Advice (Wolters Kluwer)


• alvimopan Advanced Consumer (Micromedex) - Includes Dosage Information


• Entereg Prescribing Information (FDA)


• Entereg Consumer Overview

Compare Alvimopan with other medications

• Gastrointestinal Surgery
• Postoperative Ileus

MEDIJEL GEL

1. Name Of The Medicinal Product

MEDIJEL GEL

2. Qualitative And Quantitative Composition

Lidocaine Hydrochloride BP	0.66% w/w
Aminoacridine Hydrochloride BP 1968	0.05% w/w

3. Pharmaceutical Form

Oral Gel

4. Clinical Particulars

4.1 Therapeutic Indications

The quick, effective relief from the pain of common mouth ulcers, soreness of gums and denture rubbing. Medijel Gel is administered directly onto the affected area with a clean finger or small pad of cotton wool.

4.2 Posology And Method Of Administration

The gel should be applied directly to the affected area(s) with a clean finger or small pad of cotton wool. If necessary application may be repeated after 20 minutes.

Each dose is approximately 300mg, i.e. 2mg of Lidocaine Hydrochloride and 0.15mg of Aminoacridine Hydrochloride. Medijel Gel can be used as directed for adults and children.

4.3 Contraindications

Hypersensitivity to the active substances or to any other of the ingredients.

Contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.4 Special Warnings And Precautions For Use

If symptoms persist longer than 7 days following the use of the product a doctor or dentist should be consulted.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None stated.

4.6 Pregnancy And Lactation

The safety of Medijel Gel during pregnancy and lactation has not been established, but is considered not to constitute a hazard.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Hypersensitivity reactions to Lidocaine have been reported on rare occasions.

4.9 Overdose

Maximum safe dosage for a 70kg adult is 750mg for Lidocaine (Goodman & Gilman, page 313). A tube of Medijel Gel contains 82.5mg of Lidocaine hydrochloride - overdose is not a problem.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Lidocaine Hydrochloride is well documented in Martindale 28th Edition Page 900-904 and Goodman & Gilman, Chapter 15 and pages 767-770.

Lidocaine Hydrochloride was first introduced in 1948 and is one of the most widely used local anaesthetics, producing more prompt, more intense, longer lasting and more extensive anaesthesia than does an equal concentration of procaine (Peak anaesthesia within 2-5 minutes). Local anaesthetics are drugs that block nerve conduction when applied locally to nerve tissue in appropriate concentrations. They have good powers of penetration and their action is reversible. Their use is followed by complete recovery in nerve function with no evidence of structural damage to nerve fibres or cells.

Aminoacridine Hydrochloride is a slow acting disinfectant. It exerts germicidal action against bacteria and fungi. It is also used as a surgical and endodontic irrigant and to treat local infections of the ear, mouth and throat. Its exact mode of action is not known but it involves disruption of certain metabolic pathways.

5.2 Pharmacokinetic Properties

Lidocaine is readily absorbed through mucous membranes. They exert their effects in the form of the non-ionised base. Lidocaine undergoes first-pass metabolism in the liver and bioavailability is low after administration by mouth. It is rapidly de-ethylated to the active metabolite monoethylglycinexylidide and then hydrolysed by amidases to various compounds, including glycineexylidide which has reduced activity but a longer elimination half-life. Less than 10% of a dose is excreted unchanged via the kidneys. The metabolic products are excreted in the urine.

Aminoacridine Hydrochloride if administered systematically is rapidly eliminated through the kidney (0.2 grams being eliminated from the blood in 30 minutes). (Medijel Gel dose 0.15mg Aminoacridine hydrochloride).

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Glycerol , Hydroxypolyethoxydodecane HSE, Alcohol 96% v/v, Carbomer, Sucrose, Saccharin Sodium, Peppermint Oil, Ethyl vanillin, Di-isopropanolamine 90% aqueous, Purified Water

6.2 Incompatibilities

None encountered.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Aluminium tube with membrane seal and spiked polyethylene cap.

6.6 Special Precautions For Disposal And Other Handling

N/A

7. Marketing Authorisation Holder

DDD LIMITED

94, Rickmansworth Road, Watford, Hertfordshire, United Kingdom, WDI8 7JJ.

8. Marketing Authorisation Number(S)

PL 0133/5000R

Legal Status: GSL

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of last renewal: 20/05/03

10. Date Of Revision Of The Text

March 2010

Evista

Generic Name: raloxifene (Oral route)

ral-OX-i-feen

Oral route(Tablet)

Increased risk of deep vein thrombosis and pulmonary embolism have been reported. Avoid in women with active or past history of venous thromboembolism. Increased risk of death due to stroke occurred in a trial in postmenopausal women with documented coronary heart disease or at increased risk for major coronary events .

Commonly used brand name(s)

In the U.S.

• Evista

Available Dosage Forms:

• Tablet

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Selective Estrogen Receptor Modulator

Uses For Evista

Raloxifene is used to help prevent and treat thinning of the bones (osteoporosis) only in postmenopausal women.

It works like an estrogen to stop the bone loss that can develop in women after menopause, but it does not increase the bone density as much as daily 0.625 mg doses of conjugated estrogens. Raloxifene will not treat hot flashes of menopause and may cause hot flashes to occur. Also, raloxifene does not stimulate the breast or uterus as estrogen does.

Raloxifene lowers the blood concentrations of total and low-density lipoprotein (LDL) cholesterol, the bad cholesterols, but it does not increase concentrations of high-density lipoprotein (HDL) cholesterol, the good cholesterol, in your blood.

Raloxifene is also used to lower chances of having invasive breast cancer in postmenopausal women with osteoporosis or at high risk of having invasive breast cancer .

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

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

• Breast cancer prevention in high-risk women who have already gone through menopause .

Before Using Evista

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

Allergies

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

Geriatric

This medicine has been tested only in women past menopause and has not been shown to cause different side effects or problems in elderly people than it does in adults who have just gone through menopause.

Pregnancy

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

Breast Feeding

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

Interactions with Medicines

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

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Blood clot formation, active or history of, including deep vein thrombosis, pulmonary embolism, and retinal embolism—Raloxifene may slightly increase the chances of these conditions and, if they are already present, cause them to worsen. This medicine should not be used in patients with these conditions .

• Cancer or tumors or


• Congestive heart failure or


• Heart rhythm problems (e.g., atrial fibrillation) or


• High blood pressure or


• Stroke, history of or


• Transient ischemic attack (TIA), history of or


• Any other condition that increases the risk of blood clots—Taking raloxifene while having one of these conditions may worsen the chance that blood clots can form .

• Kidney disease or


• Liver disease—These conditions may cause higher concentrations of raloxifene in the blood .

Proper Use of Evista

A paper with information for the patient will be given to you with your filled prescription, and will provide many details concerning the use of raloxifene. Read this paper carefully and ask your health care professional if you need additional information or explanation.

Many patients trying to prevent or treat bone loss will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed.

Dosing

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

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

• For oral dosage form (tablets):
  
  • For preventing bone loss:
    
    • Adults—60 mg once a day, with or without meals.
    
    
  
  
  • For treating bone loss:
    
    • Adults—60 mg once a day, with or without meals.
    
    
  
  
  • For preventing invasive breast cancer:
    
    • Adults—60 mg once a day, with or without meals .
    
    
  
  

Missed Dose

If you miss a dose of this medicine, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

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

Precautions While Using Evista

It is very important that you keep your appointments with your doctor even if you feel well.

Before you have any kind of surgery, tell the medical doctor in charge that you are using this medicine. Discuss discontinuing use of raloxifene 3 days before you think you will have a long period of inactivity, sitting, or bed rest, such as after having surgery or going on a long trip. The doctor may have you start the medicine again after you are back on your feet and fully mobile. If you are going on a trip and stay on raloxifene, you should walk regularly or move about when possible. Remaining still for long periods may cause blood clots for some people, and raloxifene may rarely worsen their condition.

If you are able to become pregnant, stop using the medicine immediately if you think you have become pregnant and check with your doctor. Raloxifene is recommended for women who are past menopause.

Raloxifene does not act like an estrogen to stimulate the uterus or breast. If you experience vaginal bleeding, breast pain or enlargement, or swelling of hands or feet while on raloxifene, you should report it to your doctor.

Other ways that may be used with raloxifene to help prevent or treat bone loss are taking calcium plus vitamin D supplements and getting weight-bearing exercise. You may want to discuss these options with your doctor.

Evista Side Effects

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

Stop taking this medicine and get emergency help immediately if any of the following effects occur:

Rare

• Coughing blood


• headache or migraine headache


• loss of or change in speech, coordination, or vision


• pain or numbness in chest, arm, or leg


• shortness of breath (unexplained)

Check with your doctor as soon as possible if any of the following side effects occur:

More common

• Bloody or cloudy urine


• chest pain


• difficult, burning, or painful urination


• fever


• frequent urge to urinate


• infection, including body aches or pain, congestion in throat, cough, dryness or soreness of throat, runny nose, and loss of voice


• leg cramping


• skin rash


• swelling of hands, ankles, or feet


• vaginal itching

Less common

• Abdominal pain (severe)


• aching body pains


• congestion in lungs


• decreased vision or other changes in vision


• diarrhea


• difficulty in breathing


• hoarseness


• loss of appetite


• nausea


• trouble in swallowing


• weakness

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

More common

• Hot flashes, including sudden sweating and feelings of warmth (especially common during the first 6 months of treatment)


• increased white vaginal discharge


• joint or muscle pain


• mental depression


• problems of stomach or intestines, including passing of gas, upset stomach, or vomiting


• swollen joints


• trouble in sleeping


• weight gain (unexplained)

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

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

See also: Evista side effects (in more detail)

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

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

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• Evista Prescribing Information (FDA)


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Integra F

Pronunciation: FER-us-FUE-ma-rate/PAHL-ee-SAAK-ah-ride EYE-urn/FOE-lik AS-id/VYE-ta-min C/VYE-ta-min B3
Generic Name: Ferrous Fumarate/Polysaccharide Iron Complex/Folic Acid/Vitamin C/Vitamin B3
Brand Name: Integra F

Accidental overdose of products that contain iron is a leading cause of fatal poisoning in children younger than 6 years old. Keep this and all medicines out of the reach of children. In case of accidental ingestion, call the poison control center or a doctor at once.

Integra F is used for:

Treating anemia caused by low levels of iron or folate in the blood. It is used during pregnancy to prevent and treat low levels of iron in the blood and to provide a maintenance dose of folic acid. It may also be used to treat other conditions as determined by your doctor.

Integra F is an iron, vitamin, and folic acid combination. It works by providing iron and folic acid to the body.

Do NOT use Integra F if:

• you are allergic to any ingredient in Integra F


• you have high levels of iron in the blood (eg, hemochromatosis, hemosiderosis)


• you have hemolytic anemia or pernicious anemia

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

Before using Integra F:

Some medical conditions may interact with Integra F. 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 any other type of anemia


• if you have stomach or bowel problems (eg, Crohn disease, diverticulitis, ulcerative colitis, peptic ulcer), the blood disease porphyria, or other blood problems (eg, thalassemia)


• if you have a bleeding problem or have had multiple blood transfusions

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

• Fluorouracil because the risk of its side effects may be increased by Integra F


• Doxycycline, hydantoins (eg, phenytoin), mycophenolate, penicillamine, or thyroid hormones (eg, levothyroxine) because their effectiveness may be decreased by Integra F

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

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

• Take Integra F by mouth on an empty stomach at least 1 hour before or 2 hours after eating. If stomach upset occurs, take with food to reduce stomach irritation.


• Do not take an antacid within 1 hour before or 2 hours after you take Integra F.


• If you also take a bisphosphonate (eg, alendronate), cefdinir, eltrombopag, methyldopa, a quinolone antibiotic (eg, ciprofloxacin), or a tetracycline antibiotic (eg, minocycline), ask your doctor or pharmacist how to take it with Integra F.


• If you miss a dose of Integra F, 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 Integra F.

Important safety information:

• Do NOT take more than the recommended dose without checking with your doctor.


• Do not take large doses of vitamins while you use Integra F unless your doctor tells you to


• Integra F has iron in it. Iron overdose is a leading cause of fatal poisoning in children younger than 6 years of age. In case of an overdose, call a doctor or poison control center right away.


• Integra F may darken the stools. This is normal and not a cause for concern.


• Integra F may interfere with certain lab tests, such as tests used to check for blood in the stool. Be sure your doctor and lab personnel know you are taking Integra F.


• Lab tests, including blood tests and iron levels, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• Integra F should not be used in CHILDREN younger than 12 years old; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Integra F while you are pregnant. If you are or will be breast-feeding while you use Integra F, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Integra F:

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:

Constipation; diarrhea; heartburn; loss of appetite; nausea; vomiting.

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); black, tarry, or bloody stools; severe or persistent stomach pain.

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 FDA at 1-800-FDA-1088 (1-800-332-1088) or at http://www.fda.gov/medwatch.

See also: Integra F 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 black, tarry, or bloody stools; blue or unusually pale skin; coma; drowsiness; severe or persistent nausea or vomiting.

Proper storage of Integra F:

Store Integra F 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 Integra F out of the reach of children and away from pets.

General information:

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


• Integra F 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 Integra F. 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 Integra F resources

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

• Integra F Prescribing Information (FDA)


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• Ferrex 28 Prescribing Information (FDA)


• FerroGels Forte Prescribing Information (FDA)


• Hematogen Forte Prescribing Information (FDA)


• Integra Plus Prescribing Information (FDA)


• Irospan 24/6 Prescribing Information (FDA)


• NovaFerrum Prescribing Information (FDA)


• Tricon Prescribing Information (FDA)

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• Anemia
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Lioresal Intrathecal

LIORESAL Intrathecal Injection 50 micrograms/1 ml

LIORESAL Intrathecal Infusion 10 mg/5 ml

LIORESAL Intrathecal Infusion 10 mg/20 ml

(baclofen)

The product will be called Lioresal Intrathecal in this leaflet

What you need to know about Lioresal Intrathecal

Your doctor has decided that you need this medicine to help treat your condition.

Please read this leaflet carefully before you start treatment. It contains important information. Keep the leaflet in a safe place because you may want to read it again.

If you have any other questions, or if there is something you don’t understand, please ask your doctor or nurse.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What Lioresal Intrathecal is and what it’s used for


• 2. Things to consider before you start Lioresal Intrathecal


• 3. Having Lioresal Intrathecal


• 4. Possible side effects


• 5. How to store Lioresal Intrathecal


• 6. Further information

What Lioresal Intrathecal is and what it’s used for

Lioresal Intrathecal contains the active ingredient, baclofen. It is administered by intrathecal injection directly into the spinal fluid. It is available in three different sizes and strengths containing either 50 micrograms in 1 ml, 10 mg in 5 ml or 10 mg in 20 ml of baclofen.

Baclofen is a muscle-relaxant drug. Lioresal Intrathecal is used to relieve muscle rigidity (spasticity) which may occur as a result of injury or illness affecting the spinal cord or the brain. This injection is used in people who haven’t responded to oral medicines or who get unacceptable side effects when they take baclofen by mouth.

Things to consider before you have a Lioresal Intrathecal injection

Some people MUST NOT have Lioresal Intrathecal. Talk to your doctor if:

• you think you may be allergic to baclofen or to any of the other ingredients of the injection. (These are listed at the end of the leaflet.)

You should also ask yourself these questions before having Lioresal Intrathecal:

• Have you understood everything the doctor or nurse has told you about the risks associated with Lioresal Intrathecal?


• Do you understand how to use the injection pump?

If you are at all confused about either of these points, please ask the doctor or nurse.

• Are you having any other injections into the spine?


• Are you suffering from any infection?


• Have you had a head injury within the last year?


• Have you ever had a crisis caused by a condition called autonomic dysreflexia? (Your doctor will be able to explain this to you.)


• Have you had a stroke?


• Do you have epilepsy?


• Do you have a stomach ulcer or any other problem with your digestion?


• Do you suffer from any mental illness?


• Are you being treated for high blood pressure?


• Do you have Parkinson’s disease?


• Do you suffer from any liver, kidney or lung disease?


• Do you have diabetes?


• Do you have difficulties in urinating?


• Are you pregnant or breast feeding?

If the answer to any of this second list of questions is YES, tell your doctor or nurse because Lioresal Intrathecal may not be the right medicine for you.

Are you taking other medicines?

Some medicines can interfere with your treatment. Remind your doctor or nurse if you are taking any of the following:

• Other medicines for your spastic condition


• Antidepressants


• Medicines for high blood pressure


• Other drugs which also affect the kidney, e.g. ibuprofen


• Medicines for Parkinson’s disease


• Medicines for epilepsy


• Opiates for pain relief.


• Medicines which slow down the nervous system, e.g. anti-histamines and sedatives. (Some of these can be bought over-the-counter.)

Always tell your doctor or nurse about all the medicines you are taking. This means medicines you have bought yourself as well as medicines on prescription from your doctor.

Will there be any problems with driving or using machinery?

Some people may feel drowsy and/or dizzy or have problems with their eyes while they are being treated with Lioresal Intrathecal. If this happens, you should not drive or do anything that requires you to be alert (such as operate tools or machinery) until these effects have worn off.

Other special warnings

• Be careful when drinking alcohol - it may affect you more than usual.



• Contact your doctor immediately if you think that Lioresal Intrathecal is not working as well as usual. It is important to make sure that there are no problems with the pump.



• Treatment with Lioresal Intrathecal must not stop suddenly because of the risk of withdrawal effects. You must make sure that you do not miss those hospital visits when the pump reservoir is being refilled.



• Your doctor may want to give you a check up from time to time while you are being treated with Lioresal Intrathecal.



• If you are going to have an operation of any kind, make sure that the doctor knows that you are being treated with Lioresal Intrathecal.

Having a Lioresal Intrathecal injection

Lioresal Intrathecal is administered by intrathecal injection. This means that the medicine is injected directly into the spinal fluid. The dose needed varies from person to person depending on their condition, and the doctor will decide what dose you need after he/she has tested your response to the drug.

First of all the doctor will find out, by giving you single doses of Lioresal Intrathecal, whether it is suitable for you. During this period your heart and lung functions will be closely monitored. If your symptoms improve, a special pump which can deliver the drug continuously, will be implanted into your chest or abdominal wall. The doctor will give you all of the information you need to use the pump and to get the correct dosage. Make sure that you understand everything.

The final dose of Lioresal Intrathecal depends on how each person responds to the drug. You will be started on a low dose, and this will be increased gradually over a few days, under the supervision of the doctor, until you are having the dose which is right for you. If the starting dose is too high, or if the dose is increased too quickly, you are more likely
to experience side effects.

To avoid unpleasant side effects which may be serious and even life-threatening, it is important that your pump does not run out. The pump must always be filled by a doctor or nurse, and you must make sure that you do not miss your clinic appointments.

You should not stop treatment suddenly. If the doctor decides to stop your treatment, the dose will be reduced gradually to prevent withdrawal symptoms such as muscle spasms and increased muscle rigidity, fast heart rate, fever, confusion, hallucinations, changes in mood and emotion, mental disorders, feeling persecuted or convulsions (fits). On rare occasions these symptoms could be life-threatening. If you or your carers notice any of these symptoms, contact your doctor immediately just in case something has gone wrong with the pump or delivery system.

During long-term treatment some patients find that Lioresal becomes less effective. You may require occasional breaks in treatment. Your doctor will advise you what to do.

Lioresal Intrathecal is not suitable for all children. The doctor will decide.

Overdose

It is very important that you, and anyone caring for you, can recognise the signs of overdose. These may appear if the pump is not working properly, and you must tell the doctor straight away.

Signs of overdose are:

• Unusual muscle weakness (too little muscle tone)


• Sleepiness


• Dizziness or light-headedness


• Excessive salivation


• Nausea or vomiting


• Difficulty in breathing


• Convulsions


• Loss of consciousness


• Abnormally low body temperature

Lioresal Intrathecal Side Effects

Lioresal Intrathecal is suitable for most people, but, like all medicines, it can sometimes cause side effects.

The side effects listed below have been reported:

More than 1 in 10 people have experienced:

Feeling tired, drowsy or weak.

Up to 1 in 10 people have experienced:

Feeling lethargic (having no energy)

Headache, dizziness or light-headedness

Pain, fever or chills

Seizures

Tingling hands or feet

Problems with eyesight

Slurred speech

Insomnia

Breathing difficulties, pneumonia

Feeling confused, anxious, agitated or depressed

Low blood pressure (fainting)

Feeling or being sick, constipation and diarrhoea

Loss of appetite, dry mouth or excessive saliva

Rash and itching, swelling of the face or hands and feet

Urinary incontinence, or problems when urinating

Cramps

Sexual problems in men, e.g. impotence.

Up to 1 in 100 people have experienced:

Feeling abnormally cold

Memory loss

Mood swings and hallucinations, feeling suicidal

Stomach ache, difficulty in swallowing, loss of taste, dehydration

Loss of muscle control

Raised blood pressure

Slow heart beat

Deep vein thrombosis

Flushed or pale skin, excessive sweating

Hair loss.

There have been rare reports of problems associated with the pump and delivery system.

There are sometimes adverse events associated with the delivery system e.g. infections or meningitis.

If any of the symptoms become troublesome, or if you notice anything else not mentioned here, please go and see your doctor. He/she may want to adjust the dose or give you a different medicine.

How to store Lioresal Intrathecal

Keep all medicines out of the reach and sight of children.

Lioresal Intrathecal should be stored below 30ºC.

They should not be used after the expiry date which is printed on the outside of the pack.

Further information

Lioresal Intrathecal is available in three different sizes and strengths containing either 50 micrograms in 1 ml, 10 mg in 5 ml or 10 mg in 20 ml of the active ingredient, baclofen.

The ampoules also contain sodium chloride and water for injections.

The product licence holder is

Novartis Pharmaceuticals UK Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

England

Lioresal Intrathecal is released onto the market by

Novartis Pharmaceuticals UK Ltd

Wimblehurst Road

Horsham

West Sussex

RH12 5AB

This leaflet was revised in April 2008.

If you would like any more information, or would like the leaflet in a different format,
please contact Medical Information at Novartis Pharmaceuticals UK Ltd, telephone number 01276 698370.

LIORESAL is a registered trade mark

Copyright Novartis Pharmaceuticals UK Limited

Rifinah 150 / 100mg and 300 / 150mg

1. Name Of The Medicinal Product

Rifinah 150/100mg Tablets

Rifinah 300/150mg Tablets

2. Qualitative And Quantitative Composition

Rifinah 150 : Rifampicin PhEur 150mg, Isoniazid PhEur 100mg

Rifinah 300 : Rifampicin PhEur 300mg, Isoniazid PhEur 150mg

3. Pharmaceutical Form

Rifinah 150 : Cyclamen, smooth, shiny, round, curved sugar coated tablet.

Rifinah 300 : Orange, smooth, shiny capsule shaped sugar coated tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

Rifinah is indicated in the treatment of all forms of tuberculosis, including fresh, advanced and chronic cases.

4.2 Posology And Method Of Administration

For oral administration.

Another antituberculosis drug may be given concurrently with Rifinah until the susceptibility of the infecting organism to rifampicin and isoniazid has been confirmed.

Adults: Patients should be given the following single daily dose preferably on an empty stomach at least 30 minutes before a meal or 2 hours after a meal:

Rifinah 150: Patients weighing less than 50kg - 3 tablets.

Rifinah 300: Patients weighing 50kg or more - 2 tablets.

Use in the elderly: Caution should be exercised in such patients especially if there is evidence of liver impairment.

4.3 Contraindications

Rifinah is contraindicated in the presence of jaundice. Rifinah is contraindicated in patients who are hypersensitive to rifamycins or isoniazid or any of the excipients.

Rifinah use is contraindicated when given concurrently with the combination of saquinavirr/ritonavir (see section 4.5 Interactions).

4.4 Special Warnings And Precautions For Use

Rifinah is a combination of 2 drugs, each of which has been associated with liver dysfunction.

All tuberculosis patients should have pre-treatment measurements of liver function.

Adults treated for tuberculosis with Rifinah should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count and a platelet count (or estimate).

Patients should be seen at least monthly during therapy and should be questioned specifically about symptoms associated with adverse reactions.

All patients with abnormalities should have follow-up, including laboratory testing, if necessary. However, because there is a higher frequency of isoniazid-associated hepatitis among persons older than 35 years of age, a transaminase measurement should be obtained at baseline and at least monthly during therapy in this age group. Other factors associated with an increased risk of hepatitis include daily use of alcohol, chronic liver disease, intravenous drug use and being a black or Hispanic woman.

If the patient has no evidence of pre-existing liver disease and normal pre-treatment liver function, liver function tests need only be repeated if fever, vomiting, jaundice or other deterioration in the patient's condition occurs.

Rifampicin

Rifampicin should be given under the supervision of a respiratory or other suitably qualified physician.

Patients with impaired liver function should only be given rifampicin in cases of necessity, and then with caution and under close medical supervision. In these patients, lower doses of rifampicin are recommended and careful monitoring of liver function, especially serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) should initially be carried out prior to therapy, weekly for two weeks, then every two weeks for the next six weeks. If signs of hepatocellular damage occur, rifampicin should be withdrawn.

Rifampicin should also be withdrawn if clinically significant changes in hepatic function occur. The need for other forms of antituberculosis therapy and a different regimen should be considered. Urgent advice should be obtained from a specialist in the management of tuberculosis. If rifampicin is re-introduced after liver function has returned to normal, liver function should be monitored daily.

In patients with impaired liver function, elderly patients, malnourished patients and possibly children under two years of age, caution is particularly recommended when instituting therapeutic regimens in which isoniazid is to be used concurrently with rifampicin.

In some patients, hyperbilirubinaemia can occur in the early days of treatment. This results from competition between rifampicin and bilirubin for hepatic excretion. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather the decision should be made after repeating the tests, noting trends in the levels and considering them in conjunction with the patient's clinical condition.

Because of the possibility of immunological reaction including anaphylaxis (see section 4.8 Undesirable effects) occurring with intermittent therapy (less than 2 to 3 times per week) patients should be closely monitored. Patients should be cautioned against interruption of dosage regimens since these reactions may occur.

Rifampicin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones and vitamin D. Isolated reports have associated porphyria exacerbation with rifampicin administration.

Isoniazid

Use of isoniazid should be carefully monitored in patients with current chronic liver disease or severe renal dysfunction.

Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after many months of treatment. The risk of developing hepatitis is age related. Therefore, patients should be monitored for the prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea or vomiting. If these symptoms appear or if signs suggestive of hepatic damage are detected, isoniazid should be discontinued promptly, since continued use of the drug in these cases has been reported to cause a more severe form of liver damage.

Care should be exercised in the treatment of elderly or malnourished patients who may also require vitamin B6 supplementation with the isoniazid therapy.

Use of isoniazid should be carefully monitored in patients with slow acetylator status, epilepsy, history of psychosis, history of peripheral neuropathy, diabetes, alcohol dependence, HIV infection or porphyria.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Food Interaction

Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g. headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g. skipjack, tuna, other tropical fish). Tyramine- and histamine-containing foods should be avoided by patients receiving Rifinah.

Interactions with Other Medicinal Products

Cytochrome P-450 enzyme interaction

Rifampicin is known to induce and isoniazid is known to inhibit certain cytochrome P-450 enzymes. In general, the impact of the competing effects of rifampicin and isoniazid on the metabolism of drugs that undergo biotransformation through the affected pathways is unknown. Therefore, caution should be used when prescribing Rifinah with drugs metabolised by cytochrome P-450. To maintain optimum therapeutic blood levels, dosages of drugs metabolised by these enzymes may require adjustment when starting or stopping Rifinah.

Rifampicin

Examples of drugs metabolised by cytochrome P-450 enzymes are:

• Antiarrhythmics (e.g. disopyramide, mexiletine, quinidine, propafenone, tocainide),

• Antiepileptics (e.g. phenytoin),

• Hormone antagonist (antiestrogens e.g. tamoxifen, toremifene, gestinone),

• Antipsychotics (e.g. haloperidol, aripiprazole),

• Anticoagulants (e.g. coumarins),

• Antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole),

• Antivirals (e.g. saquinavir, indinavir, efavirenz, amprenavir, nelfinavir, atazanavir, lopinavir, nevirapine),

• Barbiturates

• Beta-blockers (e.g. bisoprolol, propanolol),

• Anxiolytics and hypnotics (e.g. diazepam, benzodiazepines, zopiclone, zolpidem),

• Calcium channel blockers (e.g. diltiazem, nifedipine, verapamil, nimodipine, isradipine, nicardipine, nisoldipine),

• Antibacterials (e.g. chloramphenicol, clarithromycin, dapsone, doxycycline, fluoroquinolones, telithromycin),

• Corticosteroids

• Cardiac glycosides (digitoxin, digoxin),

• Clofibrate,

• Systemic hormonal contraceptives

• Oestrogen,

• Antidiabetic (e.g. chlorpropamide, tolbutamide, sulfonylureas, rosiglitazone),

• Immunosuppressive agents (e.g. ciclosporin, sirolimus, tacrolimus)

• Irinotecan,

• Thyroid hormone (e.g. levothyroxine),

• Losartan,

• Analgesics (e.g. methadone, narcotic analgesics),

• Praziquantel,

• Progestogens,

• Quinine,

• Riluzole,

• Selective 5-HT3 receptor antagonists (e.g. ondansetron)

• Statins metabolised by CYP 3A4 (e.g. simvastatin),

• Theophylline,

• Tricyclic antidepressants (e.g. amitriptyline, nortriptyline),

• Cytotoxics (e.g. imatinib),

• Diuretics (e.g. eplerenone)

Patients using oral contraceptives should be advised to change to non-hormonal methods of birth control during Rifinah therapy. Also, diabetes may become more difficult to control.

When rifampicin is given concomitantly with the combination saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of Rifinah with saquinavir/ritonavir is contraindicated (see section 4.3 Contraindications).

Other Interactions

When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampicin were observed.

Concurrent use of ketoconazole and rifampicin has resulted in decreased serum concentrations of both drugs.

Concurrent use of rifampicin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient's clinical condition.

Concomitant antacid administration may reduce the absorption of rifampicin.

Daily doses of rifampicin should be given at least 1 hour before the ingestion of antacids.

When rifampicin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of rifampicin and halothane should be avoided. Patients receiving both rifampicin and isoniazid should be monitored closely for hepatotoxicity.

When rifampicin is taken with para-aminosalicylic acid (PAS), rifampicin levels in the serum may decrease. Therefore, the drugs should be taken at least eight hours apart.

Interactions with Isoniazid

The following drugs may interact with isoniazid:

• Antiepileptics (e.g. carbamazepine and phenytoin

There may be an increased risk of distal sensory neuropathy when isoniazid is used in patients taking stavudine.

Concomitant use of zalcitabine with isoniazid has been shown to approximately double the renal clearance if isoniazid in HIV infected patients.

Administration of prednisolone 20mg to 13 slow acetylators and 13 fast acetylators for receiving isoniazid 10mg/kg reduced plasma concentrations of isoniazid by 25% and 40%, respectively. The clinical significance of this effect has not been established.

The effect of acute alcohol intake (serum levels 1g/L maintained for 12 hours) on the metabolism of isoniazid (300mg/d for 2 days) was studies in 10 healthy volunteers in a controlled cross over design. The metabolism of isoniazid and its metabolite, acetyl isoniazid, was not modified by this acute alcohol intake. The metabolism of isoniazid may be increased in chronic alcoholics; however this effect has not been quantified.

Appropriate adjustments of these drugs should be made.

Other Interactions

Para-aminosalicylic acid may increase the plasma concentration and elimination half-life of isoniazid by competing for acetylating enzymes.

General anaesthetics may increase the hepatotoxicity of isoniazid.

The absorption of isoniazid is reduced by antacids.

The risk of CNS toxicity is increased when isoniazid is given with cycloserine.

Isoniazid may reduce plasma concentration of ketoconazole and increase plasma concentration of theophylline.

Interference with laboratory and diagnostic tests

Therapeutic levels of rifampicin have been shown to inhibit standard microbiological assays for serum folate and Vitamin B12. Thus, alternative assay methods should be considered. Transient elevation of BSP and serum bilirubin has been reported. Rifampicin may impair biliary excretion of contrast media used for visualization of the gallbladder, due to competition for biliary excretion. Therefore, these tests should be performed before the morning dose of rifampicin.

4.6 Pregnancy And Lactation

Pregnancy

Rifampicin

Rifampicin has been shown to be teratogenic in rodents when given in large doses. There are no well controlled studies with Rifinah in pregnant women. Although rifampicin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampicin, alone or in combination with other antituberculosis drugs, on the human foetus is not known.

When administered during the last few weeks of pregnancy, rifampicin can cause post-natal haemorrhages in the mother and infant, for which treatment with Vitamin K1 may be indicated.

Isoniazid

It has been reported that in both rats and rabbits, isoniazid may exert an embryocardial effect when administered orally during pregnancy, although no isoniazid-related congenital anomalies have been found in reproduction studies in mammalian species (mice, rats, rabbits).

Therefore, Rifinah should be used in pregnant women or in women of child bearing potential only if the potential benefit justifies the potential risk to the foetus.

Lactation

Rifampicin and isoniazid are excreted in breast milk and infants should not be breast fed by a patient receiving Rifinah unless in the physician's judgement the potential benefit to the patient outweighs the potential risk to the infant.

In breast-fed infants whose mothers are taking isoniazid, there is a theoretical risk of convulsions and neuropathy (associated with vitamin B6 deficiency), therefore they should be monitored for early signs of these effects and consideration should be given to treating both mother and infant prophylactically with pyridoxine.

4.7 Effects On Ability To Drive And Use Machines

Isoniazid has been associated with vertigo, visual disorders and psychotic reactions (see section 4.8). Patients should be informed of these, and advised that if affected, they should not drive, operate machinery or take part in any activities where these symptoms may put either themselves or others at risk

4.8 Undesirable Effects

Rifampicin

Reactions to rifampicin occurring with either daily or intermittent dosage regimens include:

Cutaneous reactions which are mild and self-limiting may occur and do not appear to be hypersensitivity reactions. Typically they consist of flushing and itching with or without a rash. Urticaria and more serious hypersensitivity reactions occur but are uncommon. Exfoliative dermatitis, pemphigoid reaction, erythema multiforme including Stevens-Johnson syndrome, Lyells syndrome and vasculitis have been reported rarely.

Gastrointestinal reactions consist of anorexia, nausea, vomiting, abdominal discomfort, and diarrhoea. Pseudomembranous colitis has been reported with rifampicin therapy.

Hepatitis can be caused by rifampicin and liver function tests should be monitored (see section 4.4. Special warnings and precautions for use).

Central Nervous System: Psychoses have been rarely reported.

Thrombocytopenia with or without purpura may occur, usually associated with intermittent therapy, but is reversible if drug is discontinued as soon as purpura occurs. Cerebral haemorrhage and fatalities have been reported when rifampicin administration has been continued or resumed after the appearance of purpura.

Disseminated intravascular coagulation has also been rarely reported.

Eosinophilia, leucopenia, oedema, muscle weakness and myopathy have been reported to occur in a small percentage of patients treated with rifampicin.

Agranulocytosis has been reported very rarely reported.

Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.

Reactions usually occurring with intermittent dosage regimens and probably of immunological origin include:

• 'Flu Syndrome' consisting of episodes of fever, chills, headache, dizziness, and bone pain appearing most commonly during the 3rd to the 6th month of therapy. The frequency of the syndrome varies but may occur in up to 50 % of patients given once-weekly regimens with a dose of rifampicin of 25 mg/kg or more.

• Shortness of breath and wheezing.

• Decrease in blood pressure and shock.

• Anaphylaxis.

• Acute haemolytic anaemia.

• Acute renal failure usually due to acute tubular necrosis or acute interstitial nephritis.

If serious complications arise, e.g. renal failure, thrombocytopenia or haemolytic anaemia, rifampicin should be stopped and never restarted.

Occasional disturbances of the menstrual cycle have been reported in women receiving long-term antituberculosis therapy with regimens containing rifampicin.

Rifampicin may produce a reddish colouration of the urine, sweat, sputum and tears. The patient should be forewarned of this. Soft contact lenses may be permanently stained.

Isoniazid

Hypersensitivity reactions: Fever, anaphylactic reactions.

Nervous system: Vertigo; polyneuritis, presenting as paresthesia, muscle weakness, loss of tendon reflexes, etc, is unlikely to occur with the recommended daily dose of Rifinah. The incidence is higher in "slow acetylators”. Other neurotoxic effects, which are uncommon with conventional doses, are convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment and toxic psychosis. The possibility that the frequency of seizures may be increased in patients with epilepsy should be borne in mind.

Cutaneous: Rash, acne, Stevens-Johnson syndrome, exfoliative dermatitis and pemphigus.

Hematologic: Eosinophilia, agranulocytosis, thrombocytopenia, anemia, aplastic anaemia and haemolytic anaemia

Gastrointestinal: Pancreatitis, constipation, dry mouth, nausea, vomiting and epigastric distress.

Hepatic: Severe and sometimes fatal hepatitis may occur with isoniazid therapy.

Reproductive system and breast disorders: gynaecomastia

Investigations: anti-nuclear antibodies

Metabolism and Nutrition Disorders: hyperglycaemia

Miscellaneous: Pellagra, systemic lupus erythematosus-like syndrome.

4.9 Overdose

• Signs and Symptoms

Rifampicin

Nausea, vomiting, abdominal pain, pruritus, headache and increasing lethargy will probably occur within a short time after acute ingestion; unconsciousness may occur when there is severe hepatic disease. Transient increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange colouration of the skin, urine, sweat, saliva, tears and faeces will occur, and its intensity is proportional to the amount ingested. Facial or periorbital oedema has also been reported in paediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.

The minimum acute lethal or toxic dose is not well established. However, nonfatal acute overdoses in adults have been reported with doses ranging from 9 to 12 g rifampicin. Fatal acute overdoses in adults have been reported with doses ranging from 14 to 60 g. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports. Nonfatal overdoses in paediatric patients ages 1 to 4 years old of 100 mg/kg for one to two doses have been reported.

Isoniazid

Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours after ingestion. Nausea, vomiting, dizziness, slurring of speech, blurring of vision, and visual hallucinations (including bright colours and strange designs) are among the early manifestations. With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma are to be expected, along with severe, intractable seizures. Severe metabolic acidosis, acetonuria and hyperglycaemia are typical laboratory findings.

• Management:

In cases of overdosage with Rifinah, gastric lavage should be performed as soon as possible. Following evacuation of the gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting.

Intensive supportive measures should be instituted, including airway patency, and individual symptoms treated as they arise .

If acute isoniazide overdose is suspected, even in asymptomatic patients, the administration of intravenous pyridoxine (vitamin B6) should be considered. In patients with seizures not controlled with pyridoxine, anticonvulsant therapy should be administered . Sodium bicarbonate should be given to control metabolic acidosis . Haemodialysis is advised for refractory cases; if this is not available, peritoneal dialysis can be used along with forced diuresis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Rifampicin and isoniazid are active bactericidial antituberculosis drugs which are particularly active against the rapidly growing extracellular organisms and also have bactericidal activity intracellularly. Rifampicin has activity against slow- and intermittently-growing M. Tuberculosis.

Rifampicin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. Cross-resistance to rifampicin has only been shown with other rifamycins.

Isoniazid acts against actively growing tubercle bacilli.

5.2 Pharmacokinetic Properties

Rifampicin

Rifampicin is readily absorbed from the stomach and the duodenum. Peak serum concentrations of the order of 10 µg/ml occur about 2-4 hours after a dose of 10mg/kg body weight on an empty stomach.

In normal subjects the biological half-life of rifampicin in serum averages about 3 hours after a 600mg dose and increases to 5.1 hours after a 900mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2-3 hours. At a dose of up to 600 mg/day, the half-life does not differ in patients with renal failure and consequently, no dosage adjustment is required.

After absorption, rifampicin is rapidly eliminated in the bile and an enterohepatic circulation ensues. During this process, rifampicin undergoes progressive deacetylation, so that nearly all the drug in the bile is in this form in about 6 hours. This metabolite retains essentially complete antibacterial activity. Intestinal reabsorption is reduced by deacetylation and elimination is facilitated. Up to 30 % of a dose is excreted in the urine, with about half of this being unchanged drug. Absorption of rifampicin is reduced when the drug is ingested with food.

Rifampicin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampicin is about 80 % protein bound. Most of the unbound fraction is not ionized and therefore is diffused freely in tissues.

Isoniazid

After oral administration isoniazid produces peak blood levels within 1 to 2 hours which decline to 50% or less within 6 hours. Ingestion of isoniazid with food may reduce its absorption . It diffuses readily into all body fluids (cerebrospinal, pleural and ascitic fluids), tissues, organs and excreta (saliva, sputum and faeces). From 50 to 70% of a dose of isoniazid is excreted in the urine in 24 hours.

Isoniazid is metabolised primarily by acetylation and dehydrazination.. The rate of acetylation is genetically determined.

Pharmacokinetic studies in normal volunteers have been shown that the two ingredients in Rifinah have comparable bioavailability whether they are given together as individual dose forms or as Rifinah.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium lauryl sulphate, calcium stearate, sodium carboxymethylcellulose, magnesium stearate, microcrystalline cellulose, acacia, gelatin, kaolin, magnesium carbonate - light, talc, titanium dioxide (E171), colloidal silicon dioxide, polyvinylpyrollidone K30, sucrose, carnauba wax, colophony, white beeswax, hard paraffin and erythrosine (E127) (Rifinah 150) or sunset yellow (E110) (Rifinah 300).

6.2 Incompatibilities

None stated.

6.3 Shelf Life

48 months.

6.4 Special Precautions For Storage

Store below 25^oC. If it proves necessary to open a blister pack, Rifinah should be dispensed in amber glass or plastic containers. Protect from moisture.

6.5 Nature And Contents Of Container

Rifinah 150: Original packs of 84 tablets (4 weeks calendar packs).

Rifinah 300: Original packs of 56 tablets (4 weeks calendar packs).

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

Rifinah 150: PL 04425/0041

Rifinah 300: PL 04425/0042

9. Date Of First Authorisation/Renewal Of The Authorisation

19 April 1999

10. Date Of Revision Of The Text

19 March 2010

LEGAL CLASSIFICATION

POM