Ceftriaxona Mesporin may be available in the countries listed below.
Ceftriaxone disodium salt (a derivative of Ceftriaxone) is reported as an ingredient of Ceftriaxona Mesporin in the following countries:
International Drug Name Search
Class: Carbapenems
Chemical Name: (4R,5S,6S)-3-[((3S,5S)-5-[[(aminosulfonyl)amino] methyl]-3-pyrrolidinyl)thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid monohydrate.
Molecular Formula: C15H24N4O6S2
CAS Number: 148016-81-3
Brands: Doribax
Antibacterial; carbapenem β-lactam antibiotic.1 3
Treatment of complicated intra-abdominal infections caused by susceptible Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. caccae, B. thetaiotaomicron, B. uniformis, B. vulgatus, Streptococcus intermedius, S. constellatus, or Peptostreptococcus micros.1 2 10
Treatment of complicated urinary tract infections (including pyelonephritis) caused by susceptible E. coli (including cases with concurrent bacteremia) or susceptible K. pneumoniae, Proteus mirabilis, Ps. aeruginosa, or Acinetobacter baumannii.1 10
Has been used for treatment of bronchopulmonary infection in patients with cystic fibrosis who are colonized with Ps. aeruginosa or Burkholderia cepacia† (designated an orphan drug by FDA for this use).16
Has been used for treatment of nosocomial pneumonia†, including ventilator-associated pneumonia† (VAP).6 13 14
Administer by IV infusion.1
Not for administration via inhalation.1 (See Pneumonitis under Cautions.)
For solution and drug compatibility information, see Compatibility under Stability.
Use strict aseptic technique since drug product contains no preservative.1
Reconstitute vial containing 500 mg of doripenem with 10 mL of sterile water for injection or 0.9% sodium chloride injection; shake gently to provide a suspension containing 50 mg/mL.1
Reconstituted suspension is not for direct injection; must be further diluted in ≤1 hour following reconstitution.1 (See Storage under Stability.)
For a 500-mg dose, withdraw contents of the reconstituted vial with a 21-gauge needle and add it to an infusion bag containing 100 mL of 0.9% sodium chloride injection or 5% dextrose for injection to provide a solution containing 500 mg (4.5 mg/mL); gently shake until clear.1
For a 250-mg dose, withdraw contents of the reconstituted vial with a 21-gauge needle and add it to an infusion bag containing 100 mL of 0.9% sodium chloride injection or 5% dextrose for injection; gently shake until clear.1 Remove and discard 55 mL of the solution from the bag to provide a solution containing 250 mg (4.5 mg/mL).1
Administer by IV infusion over 1 hour.1
Available as doripenem monohydrate; dosage expressed in terms of doripenem.1
500 mg every 8 hours.1 Usual duration is 5–14 days; treatment may be switched to an appropriate oral anti-infective after ≥3 days, if clinical improvement has been demonstrated.1
500 mg every 8 hours.1 Usual duration is 10 days but may be extended up to 14 days for patients with concurrent bacteremia; treatment may be switched to an appropriate oral anti-infective after ≥3 days, if clinical improvement has been demonstrated.1
No specific dosage recommendations at this time.1
Dosage adjustment recommended in patients with Clcr ≤50 mL/minute.1
Clcr (mL/minute) | Daily Dosage |
|---|---|
30–50 | 250 mg every 8 hours |
11–29 | 250 mg every 12 hours |
Insufficient data to recommend dosage adjustments in patients undergoing hemodialysis.1
No dosage adjustments except those related to renal impairment.1 (See Renal Impairment under Dosage and Administration.)
Known hypersensitivity to doripenem or other carbapenems.1
History of anaphylactic reaction to β-lactams.1
Treatment with anti-infectives may permit overgrowth of Clostridium difficile.1 19 20 21 22 23 C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives and may range in severity from mild diarrhea to fatal colitis.1
Consider CDAD if diarrhea develops during or after therapy and manage accordingly.1 19 20 21 22 23 Obtain a careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.1
If CDAD is suspected or confirmed, the anti-infective may need to be discontinued.1 Manage moderate to severe cases with fluid, electrolyte, and protein supplementation; appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin); and surgical evaluation when clinically indicated.1 19 20 21 22 23
Use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.1
Use results of culture and in vitro susceptibility testing.1 If such data are unavailable, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1
Pneumonitis reported following administration by inhalation†;1 not for inhalation administration.1
Doripenem reduces valproic acid serum concentrations to subtherapeutic concentrations; possible increased risk of seizures.a Monitor serum valproic acid concentrations and consider alternative therapies.a (See Specific Drugs under Interactions.)
Serious and occasionally fatal hypersensitivity reactions (e.g., anaphylaxis) and serious skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) reported.1
If hypersensitivity occurs, discontinue doripenem and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, IV fluids, IV antihistamines, pressor amines, oxygen and maintenance of an adequate airway).1
Cross-allergenicity occurs among β-lactam antibiotics, including penicillins, cephalosporins, and other β-lactams.1
Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to doripenem, cephalosporins, penicillins, or other drugs.1
Seizures and other CNS effects (e.g., confusional states, myoclonic activity) reported with carbapenems (e.g., ertapenem, imipenem, meropenem), especially in those with underlying CNS disorders (e.g., brain lesions, history of seizures) and/or compromised renal function.8 10 24 25 26
Rarely, seizures reported in patients receiving doripenem;1 causality not established.1
Category B.1
Not known if doripenem is distributed into milk.1 Use with caution.1
Safety and efficacy not established in patients <18 years of age.1
No substantial differences in safety relative to younger adults, but increased sensitivity cannot be ruled out.1
Substantially eliminated by kidneys; risk of adverse reactions may be greater in geriatric patients with impaired renal function or prerenal azotemia.1 Select dosage with caution and assess renal function periodically since geriatric patients are more likely to have renal impairment.1
Pharmacokinetics not established but impact of hepatic impairment should be minimal.1
Increased AUC.1 Dosage adjustments and monitoring of renal function recommended in patients with moderate or severe renal impairment (Clcr ≤50 mL/minute).1 (See Special Populations under Dosage and Administration.)
Risk of adverse reactions may be greater in patients with impaired renal function.1
Headache, nausea, diarrhea, rash, phlebitis.1
Does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A11.1 Not expected to induce CYP1A2, 2B6, 2C9, 2C19, or 3A4/5.1 Pharmacokinetic interactions unlikely with drugs metabolized by these isoenzymes.1
Not expected to induce UGT 1A1;1 pharmacokinetic interactions unlikely with drugs metabolized by this enzyme.1
Drug | Interaction | Comments |
|---|---|---|
Anti-infective agents (e.g., amikacin, co-trimoxazole, daptomycin, levofloxacin, linezolid, vancomycin) | Minimal potential to antagonize or be antagonized by other anti-infectives1 10 | |
Probenecid | Decreased renal tubular secretion of doripenem; increased doripenem concentrations, AUC, and prolonged half-life1 | Concomitant use not recommended1 |
Valproic acid | Concomitant administration decreases valproic acid to subtherapeutic concentrations; AUC reduced by 63% a Pharmacokinetics of doripenem unaffecteda | Monitor serum valproic acid concentrations if administered concomitantly;a consider alternative anti-infective or anticonvulsant therapya |
Distributed into intra-abdominal tissues and fluids (e.g., retroperitoneal fluid,1 peritoneal exudate,1 11 bile,1 gallbladder tissue,1 urine).1
Not known if doripenem is distributed into milk.1
Approximately 8.1%.1
Partially metabolized to an inactive ring-opened metabolite (doripenem M1) principally via dehydropeptidase-I.1
Not metabolized by CYP isoenzymes.1
Excreted principally in urine as unchanged drug (70%).1
Approximately 1 hour.1
Pharmacokinetics in patients with hepatic impairment not established.1
Removed by hemodialysis.1
AUC increased in patients with renal impairment.1
25°C (may be exposed to 15–30°C).1
Reconstituted suspension containing 50 mg/mL, in sterile water for injection or 0.9% sodium chloride injection, is stable for ≤1 hour; do not freeze.1
Diluted IV solutions prepared using 0.9% sodium chloride injection or 5% dextrose for injection are stable for 8 or 4 hours, respectively, at room temperature (including infusion time) or 24 hours at 2–8°C (including infusion time); do not freeze.1
For information on systemic interactions resulting from concomitant use, see Interactions.
Compatible |
|---|
Dextrose 5% in water |
Sodium chloride 0.9% |
Sterile water for injection |
Compatibility with other drugs not established.1 Do not mix with or add to solutions containing other drugs.1
Synthetic carbapenem β-lactam antibiotic; structurally and pharmacologically related to ertapenem, imipenem, and meropenem.1 3
Usually bactericidal in action.1
Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis.1 3 10
Spectrum of activity includes many aerobic and anaerobic gram-positive and gram-negative bacteria.1 3 4 5 10
Reported as more active than some other carbapenems against Enterobacteriaceae and Ps. aeruginosa.2 3 4 9 10 12 18
Gram-positive aerobes: Active in vitro and in clinical infections against Streptococcus intermedius1 and S. constellatus.1 Also active in vitro against Staphylococcus aureus (including oxacillin-susceptible [methicillin-susceptible] strains),1 4 S. epidermidis,4 S. agalactiae (group B streptococci),1 4 and S. pyogenes (group A β-hemolytic streptococci).1 Oxacillin-resistant (methicillin-resistant) staphylococci are resistant.1
Gram-negative aerobes: Active in vitro and in clinical infections against E. coli,1 4 Klebsiella pneumoniae,1 4 Proteus mirabilis,1 4 Ps. aeruginosa,1 4 and Acinetobacter baumannii.1 Also active in vitro against Citrobacter freundii,1 Enterobacter cloacae,1 4 E. aerogenes,1 4 K. oxytoca,1 4 Morganella morganii,1 and Serratia marcescens1 and some strains of Burkholderia cepacia.17 18
Anaerobes: Active in vitro and in clinical infections against Bacteroides fragilis,1 4 5 B. caccae,1 4 B. thetaiotaomicron,1 4 5 B. uniformis,1 4 B. vulgatus,1 4 and Peptostreptococcus micros.1 4 5
Cross-resistance may occur with other carbapenems; however, some isolates (e.g., some strains of Ps. aeruginosa) resistant to other carbapenems may be susceptible to doripenem.1 4
Advise patients that antibacterials (including doripenem) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1
Importance of completing full course of therapy, even if feeling better after a few days.1
Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with doripenem or other antibacterials in the future.1
Importance of informing clinicians of any previous hypersensitivity reactions to doripenem, other carbapenems, β-lactams, or other allergens.1
Importance of discontinuing therapy and informing clinician if an allergic or hypersensitivity reaction occurs.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.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.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion | 500 mg (of doripenem) | Doribax | Ortho-McNeil |
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
1. Ortho-McNeil, Inc. Doribax (doripenem for injection) prescribing information. Raritan, NJ; 2008 Jan.
2. Lucasti C, Jasovich A, Umeh O et al. Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double-blind, noninferiority study. Clin Ther. 2008; 30:868-83. [PubMed 18555934]
3. Zhanel GG, Wiebe R, Dilay L et al. Comparative review of the carbapenems. Drugs. 2007; 67:1027-52. [PubMed 17488146]
4. Goldstein EJ, Citron DM, Merriam CV et al. In vitro activities of doripenem and six comparator drugs against 423 aerobic and anaerobic bacterial isolates from infected diabetic foot wounds. Antimicrob Agents Chemother. 2008; 52:761-6. [PubMed 18070958]
5. Wexler HM, Engel AE, Glass D et al. In vitro activities of doripenem and comparator agents against 364 anaerobic clinical isolates. Antimicrob Agents Chemother. 2005; 49:4413-7. [PubMed 16189137]
6. Ortho-McNeil, Inc, Titusville, NJ: Personal communication.
7. Naber K, Redman R, Kotey P et al. Intravenous therapy with doripenem versus levofloxacin with an option for oral step-down therapy in the treatment of complicated urinary tract infections and pyelonephritis. Int J Antimicrob Agents. 2007; 29:S212.
8. Horiuchi M, Kimura M, Tokumura M et al. Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with beta-lactam antibiotics. Toxicology. 2006; 222:114-24. [PubMed 16549226]
9. Hagerman JK, Knechtel SA, Klepser ME. Doripenem: a new extended-spectrum carbapenem antibiotic. Formulary. 2007; 42:676-88.
10. Nicolau DP. Carbapenems: a potent class of antibiotics. Expert Opin Pharmacother. 2008; 9:23-37. [PubMed 18076336]
11. Ikawa K, Morikawa N, Urakawa N et al. Peritoneal penetration of doripenem after intravenous administration in abdominal-surgery patients. J Antimicrob Chemother. 2007; 60:1395-7. [PubMed 17884833]
12. Mesaros N, Nordmann P, Plésiat P et al. Pseudomonas aeruginosa: resistance and therapeutic options at the turn of the new millennium. Clin Microbiol Infect. 2007; 13:560-78. [PubMed 17266725]
13. Réa-Neto A, Niederman M, Lobo SM et al. Efficacy and safety of doripenem versus piperacillin/tazobactam in nosocomial pneumonia: a randomized, open-label, multicenter study. Curr Med Res Opin. 2008; 24:2113-26. [PubMed 18549664]
14. Chastre J, Wunderink R, Prokocimer P et al. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: a multicenter, randomized study. Crit Care Med. 2008; 36:1089-96. [PubMed 18379232]
15. Davies TA, Shang W, Bush K et al. Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2008; 52:1510-2. [PubMed 18250190]
16. 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; 2004 July. From FDA web site (). Accessed August 2008.
17. Chen Y, Garber E, Zhao Q et al. In vitro activity of doripenem (S-4661) against multidrug-resistant gram-negative bacilli isolated from patients with cystic fibrosis. Antimicrob Agents Chemother. 2005; 49:2510-1. [PubMed 15917558]
18. Traczewski MM, Brown SD. In vitro activity of doripenem against Pseudomonas aeruginosa and Burkholderia cepacia isolates from both cystic fibrosis and non-cystic fibrosis patients. Antimicrob Agents Chemother. 2006; 50:819-21. [PubMed 16436756]
19. Johnson S, Gerding DN. Clostridium difficile-associated diarrhea. Clin Infect Dis. 1998; 26:1027-36. [IDIS 407733] [PubMed 9597221]
20. Gerding DN, Johnson S, Peterson LR et al for the Society for Healthcare Epidemiology of America. Position paper on Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol. 1995; 16:459-77. [PubMed 7594392]
21. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. Am J Gastroenterol. 1997; 92:739-50. [IDIS 386628] [PubMed 9149180]
22. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile-associated disease. Am J Health-Syst Pharm. 1998; 55:1407-11. [IDIS 407213] [PubMed 9659970]
23. Wilcox MH. Treatment of Clostridium difficile infection. J Antimicrob Chemother. 1998; 41(Suppl C):41-6. [IDIS 407246] [PubMed 9630373]
24. Merck & Co., Inc. Invanz (ertapenem) for injection prescribing information. Whitehouse Station, NJ; 2008 Feb.
25. Merck & Co., Inc. Primaxin I.V. (imipenem and cilastatin) for injection prescribing information. Whitehouse Station, NJ; 2007 Dec.
26. AstraZeneca. Merrem I.V. (meropenem) for injection for intravenous use only prescribing information. Wilmington, DE; 2008 Mar.
27. A multicenter, phase 3 study to confirm the safety and efficacy of intravenous doripenem in complicated lower urinary tract infection or pyelonephritis (JNJ-38 174942 DORI-06 CR005398). From National Institutes of Health clinical trials website (). Accessed 2008 Sep 26.
a. Ortho-McNeil, Inc. Doribax (doripenem for injection) prescribing information. Raritan, NJ; 2008 Oct.
Bénazépril Hydrochlorothiazide EG may be available in the countries listed below.
Benazepril hydrochloride (a derivative of Benazepril) is reported as an ingredient of Bénazépril Hydrochlorothiazide EG in the following countries:
Hydrochlorothiazide is reported as an ingredient of Bénazépril Hydrochlorothiazide EG in the following countries:
International Drug Name Search
Relieving symptoms of sinus congestion, runny nose, sneezing, itchy nose or throat, itchy or watery eyes, and cough due to colds, upper respiratory infections, and allergies. It may also be used for other conditions as determined by your doctor.
Donatussin DM Suspension is a decongestant, antihistamine, and cough suppressant combination. The decongestant works by constricting blood vessels and reducing swelling in the nasal passages. The antihistamine works by blocking the action of histamine, which helps reduce symptoms such as watery eyes and sneezing. The cough suppressant works in the brain to help decrease the cough reflex to reduce a dry cough.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Donatussin DM Suspension. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Donatussin DM 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.
Ask your health care provider any questions you may have about how to use Donatussin DM 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:
Constipation; diarrhea; dizziness; drowsiness; dry mouth, nose, or throat; excitability; headache; loss of appetite; nausea; nervousness or anxiety; trouble sleeping; upset stomach; vomiting; weakness.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); confusion; difficulty urinating or inability to urinate; fast or irregular heartbeat; fever, chills, or persistent sore throat; hallucinations; loss of coordination; mental or mood changes (eg, depression); seizures; severe dizziness, drowsiness, lightheadedness, or headache; severe dryness of mouth, nose, and throat; severe or persistent trouble sleeping; shortness of breath; tremor; unusual bruising or bleeding; unusual tiredness or weakness; vision problems (eg, double vision, severe or persistent blurred vision).
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.
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include blurred vision; confusion; flushing; hallucinations; mental or mood changes; muscle spasms; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; trouble breathing; unusually fast, slow, or irregular heartbeat; vomiting.
Store Donatussin DM Suspension at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Do not freeze. Store away from heat and light. Keep Donatussin DM Suspension out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Donatussin DM 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.
Stimulating or improving breathing in patients after surgery or overdose of certain medicines. It is also used to treat chronic lung disease associated with excessive carbon dioxide in the blood.
Dopram is an analeptic. It works by stimulating the breathing center of the brain by altering the natural chemicals (neurotransmitters) in the brain.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Dopram. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Dopram. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Dopram 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.
Use Dopram as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Dopram.
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:
Abnormal skin sensations; coughing; diarrhea; dilation of pupils; dizziness; fear; flushing; headache; hiccups; itching; nausea; sweating; vomiting.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); changes in heart rate; chest pain; disorientation; fainting; fast or irregular heartbeat; fever; hyperactivity; inability to urinate; involuntary movements; loss of bladder control; muscle spasms; seizures; severe dizziness or headache; slow breathing.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: Dopram side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include agitation; confusion; cough; difficulty breathing; fast heartbeat; high blood pressure; muscle hyperactivity; reflex changes; sweating.
Dopram is usually handled and stored by a health care provider. If you are using Dopram at home, store Dopram as directed by your pharmacist or health care provider.
This information is a summary only. It does not contain all information about Dopram. 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.
Stalevo 50 mg/12.5 mg/200 mg film-coated tablets
Each tablet contains 50 mg of levodopa, 12.5 mg of carbidopa and 200 mg of entacapone.
Excipient: Each tablet contains 1.2 mg of sucrose.
For a full list of excipients, see section 6.1.
Film-coated tablet
Brownish or greyish red, round, convex, unscored film-coated tablets marked with 'LCE 50' on one side.
Stalevo is indicated for the treatment of adult patients with Parkinson's disease and end-of-dose motor fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment.
Each tablet is to be taken orally either with or without food (see section 5.2). One tablet contains one treatment dose and the tablet may only be administered as whole tablets.
The optimum daily dose must be determined by careful titration of levodopa in each patient. The daily dose should be preferably optimised using one of the six available tablet strengths (50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg 150 mg/37.5 mg/200 mg or 200 mg/50 mg/200 mg levodopa/carbidopa/entacapone).
Patients should be instructed to take only one Stalevo tablet per dose administration. Patients receiving less than 70-100 mg carbidopa a day are more likely to experience nausea and vomiting. While the experience with total daily dose greater than 200 mg carbidopa is limited, the maximum recommended daily dose of entacapone is 2,000 mg and therefore the maximum dose is 10 tablets per day for the Stalevo strengths of 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg and 150 mg/37.5 mg/200 mg. Ten tablets of Stalevo 150 mg/37.5 mg/200 mg equals 375 mg of carbidopa a day. According to this daily carbidopa dose, the maximum recommended daily Stalevo 200 mg/50 mg/200 mg dose is 7 tablets per day.
Usually Stalevo is to be used in patients who are currently treated with corresponding doses of standard release levodopa/DDC inhibitor and entacapone.
How to transfer patients taking levodopa/DDC inhibitor (carbidopa or benserazide) preparations and entacapone tablets to Stalevo
a. Patients who are currently treated with entacapone and with standard release levodopa/carbidopa in doses equal to Stalevo tablet strengths can be directly transferred to corresponding Stalevo tablets.
For example, a patient taking one tablet of 50 mg/12.5 mg of levodopa/carbidopa with one tablet of entacapone 200 mg four times daily can take one 50 mg/12.5 mg/200 mg Stalevo tablet four times daily in place of their usual levodopa/carbidopa and entacapone doses.
b. When initiating Stalevo therapy for patients currently treated with entacapone and levodopa/carbidopa in doses not equal to Stalevo 50 mg/12.5 mg/200 mg, (or 75 mg/18.75 mg/200 mg or 100 mg/25 mg/200 mg or 125 mg/31.25 mg/200 mg or 150 mg/37.5 mg/200 mg or 200 mg/50 mg/200 mg) tablets, Stalevo dosing should be carefully titrated for optimal clinical response. At the initiation, Stalevo should be adjusted to correspond as closely as possible to the total daily dose of levodopa currently used.
c. When initiating Stalevo in patients currently treated with entacapone and levodopa/benserazide in a standard release formulation, discontinue dosing of levodopa/benserazide the previous night, and start Stalevo the next morning. Begin with a dose of Stalevo that will provide either the same amount of levodopa or slightly (5-10%) more.
How to transfer patients not currently treated with entacapone to Stalevo
Initiation of Stalevo may be considered at corresponding doses to current treatment in some patients with Parkinson's disease and end-of-dose motor fluctuations, who are not stabilised on their current standard release levodopa/DDC inhibitor treatment. However, a direct switch from levodopa/DDC inhibitor to Stalevo is not recommended for patients who have dyskinesias or whose daily levodopa dose is above 800 mg. In such patients it is advisable to introduce entacapone treatment as a separate treatment (entacapone tablets) and adjust the levodopa dose if necessary, before switching to Stalevo.
Entacapone enhances the effects of levodopa. It may therefore be necessary, particularly in patients with dyskinesia, to reduce levodopa dose by 10-30% within the first days to first weeks after initiating Stalevo treatment. The daily dose of levodopa can be reduced by extending the dosing intervals and/or by reducing the amount of levodopa per dose, according to the clinical condition of the patient.
Dose adjustment during the course of the treatment
When more levodopa is required, an increase in the frequency of doses and/or the use of an alternative strength of Stalevo should be considered, within the dose recommendations.
When less levodopa is required, the total daily dose of Stalevo should be reduced either by decreasing the frequency of administration by extending the time between doses, or by decreasing the strength of Stalevo at an administration.
If other levodopa products are used concomitantly with a Stalevo tablet, the maximum dose recommendations should be followed.
Discontinuation of Stalevo therapy: If Stalevo treatment (levodopa/carbidopa/entacapone) is discontinued and the patient is transferred to levodopa/DDC inhibitor therapy without entacapone, it is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms.
Children and adolescents: Stalevo is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
Elderly: No dose adjustment of Stalevo is required for elderly patients.
Hepatic impairment: It is advised that Stalevo should be administered cautiously to patients with mild to moderate hepatic impairment. Dose reduction may be needed (see section 5.2). For severe hepatic impairment see section 4.3.
Renal impairment: Renal impairment does not affect the pharmacokinetics of entacapone. No particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with renal insufficiency, therefore Stalevo therapy should be administered cautiously to patients in severe renal impairment including those receiving dialysis therapy (see section 5.2).
- Hypersensitivity to the active substances or to any of the excipients.
- Severe hepatic impairment.
- Narrow-angle glaucoma.
- Pheochromocytoma.
- Concomitant use of Stalevo with non-selective monoamine oxidase (MAO-A and MAO-B) inhibitors (e.g. phenelzine, tranylcypromine).
- Concomitant use of a selective MAO-A inhibitor and a selective MAO-B inhibitor (see section 4.5).
- A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic rhabdomyolysis.
- Stalevo is not recommended for the treatment of drug-induced extrapyramidal reactions
- Stalevo therapy should be administered cautiously to patients with ischemic heart disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal or endocrine disease, history of peptic ulcer disease or history of convulsions.
- In patients with a history of myocardial infarction who have residual atrial nodal or ventricular arrhythmias; cardiac function should be monitored with particular care during the period of initial dose adjustments.
- All patients treated with Stalevo should be monitored carefully for the development of mental changes, depression with suicidal tendencies, and other serious antisocial behaviour. Patients with past or current psychosis should be treated with caution.
- Concomitant administration of antipsychotics with dopamine receptor-blocking properties, particularly D2 receptor antagonists should be carried out with caution, and the patient carefully observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms.
- Patients with chronic wide-angle glaucoma may be treated with Stalevo with caution, provided the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in intra-ocular pressure.
- Stalevo may induce orthostatic hypotension. Therefore Stalevo should be given cautiously to patients who are taking other medicinal products which may cause orthostatic hypotension.
- Entacapone in association with levodopa has been associated with somnolence and episodes of sudden sleep onset in patients with Parkinson's disease and caution should therefore be exercised when driving or operating machines (see section 4.7).
- In clinical studies, dopaminergic adverse reactions, e.g. dyskinesia, were more common in patients who received entacapone and dopamine agonists (such as bromocriptine), selegiline or amantadine compared to those who received placebo with this combination. The doses of other antiparkinsonian medicinal products may need to be adjusted when Stalevo treatment is substituted for a patient currently not treated with entacapone.
- Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has been observed rarely in patients with Parkinson's disease. Therefore, any abrupt dose reduction or withdrawal of levodopa should be carefully observed, particularly in patients who are also receiving neuroleptics. NMS, including rhabdomyolysis and hyperthermia, is characterised by motor symptoms (rigidity, myoclonus, tremor), mental status changes (e.g., agitation, confusion, coma), hyperthermia, autonomic dysfunction (tachycardia, labile blood pressure) and elevated serum creatine phosphokinase. In individual cases, only some of these symptoms and/or findings may be evident. The early diagnosis is important for the appropriate management of NMS. A syndrome resembling the neuroleptic malignant syndrome including muscular rigidity, elevated body temperature, mental changes and increased serum creatine phosphokinase has been reported with the abrupt withdrawal of antiparkinsonian agents. Neither NMS nor rhabdomyolysis have been reported in association with entacapone treatment from controlled trials in which entacapone was discontinued abruptly. Since the introduction of entacapone into the market, isolated cases of NMS have been reported, especially following abrupt reduction or discontinuation of entacapone and other concomitant dopaminergic medicinal products. When considered necessary, the replacement of Stalevo with levodopa and DDC inhibitor without entacapone or other dopaminergic treatment should proceed slowly and an increase in levodopa dose may be necessary.
- If general anaesthesia is required, therapy with Stalevo may be continued for as long as the patient is permitted to take fluids and medicinal products by mouth. If therapy has to be stopped temporarily, Stalevo may be restarted as soon as oral medicinal products can be taken at the same daily dose as before.
- Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended during extended therapy with Stalevo.
- For patients experiencing diarrhoea, a follow-up of weight is recommended in order to avoid potential excessive weight decrease. Prolonged or persistent diarrhoea appearing during use of entacapone may be a sign of colitis. In the event of prolonged or persistent diarrhoea, the drug should be discontinued and appropriate medical therapy and investigations considered.
- Pathological gambling, increased libido and hypersexuality have been reported in Parkinson's disease patients treated with dopamine agonists and other dopaminergic treatments such as Stalevo.
- For patients who experience progressive anorexia, asthenia and weight decrease within a relatively short period of time, a general medical evaluation including liver function should be considered.
- Stalevo contains sucrose, and therefore patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Other antiparkinsonian medicinal products: To date there has been no indication of interactions that would preclude concurrent use of standard antiparkinsonian medicinal products with Stalevo therapy. Entacapone in high doses may affect the absorption of carbidopa. However, no interaction with carbidopa has been observed with the recommended treatment schedule (200 mg of entacapone up to 10 times daily). Interactions between entacapone and selegiline have been investigated in repeated dose studies in Parkinson's disease patients treated with levodopa/DDC inhibitor and no interaction was observed. When used with Stalevo, the daily dose of selegiline should not exceed 10 mg.
Caution should be exercised when the following active substances are administered concomitantly with levodopa therapy.
Antihypertensives: Symptomatic postural hypotension may occur when levodopa is added to the treatment of patients already receiving antihypertensives. Dose adjustment of the antihypertensive agent may be required.
Antidepressants: Rarely, reactions including hypertension and dyskinesia have been reported with the concomitant use of tricyclic antidepressants and levodopa/carbidopa. Interactions between entacapone and imipramine and between entacapone and moclobemide have been investigated in single dose studies in healthy volunteers. No pharmacodynamic interactions were observed. A significant number of Parkinson's disease patients have been treated with the combination of levodopa, carbidopa and entacapone with several active substances including MAO-A inhibitors, tricyclic antidepressants, noradrenaline reuptake inhibitors such as desipramine, maprotiline and venlafaxine and medicinal products that are metabolised by COMT (e.g. catechol-structured compounds, paroxetine). No pharmacodynamic interactions have been observed. However, caution should be exercised when these medicinal products are used concomitantly with Stalevo (see sections 4.3 and 4.4).
Other active substances: Dopamine receptor antagonists (e.g. some antipsychotics and antiemetics), phenytoin and papaverine may reduce the therapeutic effect of levodopa. Patients taking these medicinal products with Stalevo should be carefully observed for loss of therapeutic response.
Due to entacapone's affinity to cytochrome P450 2C9 in vitro (see section 5.2), Stalevo may potentially interfere with active substances whose metabolism is dependent on this isoenzyme, such as S-warfarin. However, in an interaction study with healthy volunteers, entacapone did not change the plasma levels of S-warfarin, while the AUC for R-warfarin increased on average by 18% [CI90 11-26%]. The INR values increased on average by 13% [CI90 6-19%]. Thus, a control of INR is recommended when Stalevo is initiated for patients receiving warfarin.
Other forms of interactions: Since levodopa competes with certain amino acids, the absorption of Stalevo may be impaired in some patients on high protein diet.
Levodopa and entacapone may form chelates with iron in the gastrointestinal tract. Therefore, Stalevo and iron preparations should be taken at least 2-3 hours apart (see section 4.8).
In vitro data: Entacapone binds to human albumin binding site II which also binds several other medicinal products, including diazepam and ibuprofen. According to in vitro studies, significant displacement is not anticipated at therapeutic concentrations of the medicinal products. Accordingly, to date there has been no indication of such interactions.
There are no adequate data from the use of the combination of levodopa/carbidopa/entacapone in pregnant women. Studies in animals have shown reproductive toxicity of the separate compounds (see section 5.3). The potential risk for humans is unknown. Stalevo should not be used during pregnancy unless the benefits for the mother outweigh the possible risks to the foetus.
Levodopa is excreted in human breast milk. There is evidence that lactation is suppressed during treatment with levodopa. Carbidopa and entacapone were excreted in milk in animals but is not known whether they are excreted in human breast milk. The safety of levodopa, carbidopa or entacapone in the infant is not known. Women should not breast-feed during treatment with Stalevo.
Stalevo may have major influence on the ability to drive and use machines. Levodopa, carbidopa and entacapone together may cause dizziness and symptomatic orthostatism. Therefore, caution should be exercised when driving or using machines.
Patients being treated with Stalevo and presenting with somnolence and/or sudden sleep onset episodes must be instructed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes have resolved (see section 4.4).
a. Summary of the safety profile
The most frequently reported adverse reactions with Stalevo are dyskinesias occurring in approximately 19% of patients; gastrointestinal symptoms including nausea and diarrhoea occurring in approximately 15% and 12% of patients, respectively; muscle, musculoskeletal and connective tissue pain occurring in approximately 12% of patients; and harmless reddish-brown discolouration of urine (chromaturia) occurring in approximately 10% of patients. Serious events of gastrointestinal haemorrhage (uncommon) and angioedema (rare) have been identified from the clinical trials with Stalevo or entacapone combined with levodopa/DDC inhibitor. Serious hepatitis with mainly cholestatic features, rhabdomyolysis and neuroleptic malignant syndrome may occur with Stalevo although no cases have been identified from the clinical trial data.
b. Tabulated list of adverse reactions
The following adverse reactions, listed in Table 1, have been accumulated both from a pooled data of eleven double-blind clinical trials consisting of 3230 patients (1810 treated with Stalevo or entacapone combined with levodopa/DDC inhibitor, and 1420 treated with placebo combined with levodopa/DDC inhibitor or cabergoline combined with levodopa/ DDC inhibitor), and from the post-marketing data since the introduction of entacapone into the market for the combination use of entacapone with levodopa/DDC inhibitor.
Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (
Table 1. Adverse reactions
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*Adverse reactions that are mainly attributable to entacapone or are more frequent (by the frequency difference of at least 1% in the clinical trial data) with entacapone than levodopa/DDC inhibitor alone. See section c.
**The incidence rates of myocardial infarction and other ischemic heart disease events (0.43% and 1.54%, respectively) are derived from an analysis of 13 double-blind studies involving 2082 patients with end-of-dose motor fluctuations receiving entacapone.
Convulsions have occurred rarely with levodopa/carbidopa; however a causal relationship to levodopa/carbidopa therapy has not been established.
Parkinson's disease patients treated with dopamine agonists and other dopaminergic treatments such as Stalevo, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido, hypersexuality and other urges, generally reversible upon reduction of the dose or treatment discontinuation.
Entacapone in association with levodopa has been associated with isolated cases of excessive daytime somnolence and sudden sleep onset episodes.
Levodopa/carbidopa may cause false positive result when a dipstick is used to test for urinary ketone and this reaction is not altered by boiling the urine sample. The use of glucose oxidase methods may give false negative results for glycosuria.
c. Description of selected adverse reactions
Adverse reactions that are mainly attributable to entacapone or are more frequent with entacapone than levodopa/DDC inhibitor alone are indicated with an asterisk in Table 1, section 4.8b. Some of these adverse reactions relate to the increased dopaminergic activity (e.g. dyskinesia, nausea and vomiting) and occur most commonly at the beginning of the treatment. Reduction of levodopa dose decreases the severity and frequency of these dopaminergic reactions. Few adverse reactions are known to be directly attributable to the active substance entacapone including diarrhoea and reddish-brown discolouration of urine. Entacapone may in some cases cause also discolouration of e.g. skin, nail, hair and sweat. Other adverse reactions with an asterisk in Table 1, section 4.8b are marked based on either their more frequent occurring (by the frequency difference of at least 1%) in the clinical trial data with entacapone than levodopa/DDCI alone or the individual case safety reports received after the introduction of entacapone into the market.
The post-marketing data includes isolated cases of overdose in which the reported highest daily doses of levodopa and entacapone have been at least 10,000 mg and 40,000 mg, respectively. The acute symptoms and signs in these cases of overdose included agitation, confusional state, coma, bradycardia, ventricular tachycardia, Cheyne-Stokes respiration, discolourations of skin, tongue and conjunctiva, and chromaturia. Management of acute overdose with Stalevo therapy is similar to acute overdose with levodopa. Pyridoxine, however, is not effective in reversing the actions of Stalevo. Hospitalisation is advised and general supportive measures should be employed with immediate gastric lavage and repeated doses of charcoal over time. This may hasten the elimination of entacapone in particular by decreasing its absorption/reabsorption from the GI tract. The adequacy of the respiratory, circulatory and renal systems should be carefully monitored and appropriate supportive measures employed. ECG monitoring should be started and the patient carefully monitored for the possible development of arrhythmias. If required, appropriate anti-arrhythmic therapy should be given. The possibility that the patient has taken other active substances in addition to Stalevo should be taken into consideration. The value of dialysis in the treatment of overdose is not known.
Pharmacotherapeutic group: dopa and dopa derivatives, ATC code: N04BA03
According to the current understanding, the symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Dopamine does not cross the blood-brain barrier. Levodopa, the precursor of dopamine, crosses the blood brain barrier and relieves the symptoms of the disease. As levodopa is extensively metabolised in the periphery, only a small portion of a given dose reaches the central nervous system when levodopa is administered without metabolic enzyme inhibitors.
Carbidopa and benserazide are peripheral DDC inhibitors which reduce the peripheral metabolism of levodopa to dopamine, and thus, more levodopa is available to the brain. When decarboxylation of levodopa is reduced with the co-administration of a DDC inhibitor, a lower dose of levodopa can be used and the incidence of undesirable effects such as nausea is reduced.
With inhibition of the decarboxylase by a DDC inhibitor, catechol-O-methyltransferase (COMT) becomes the major peripheral metabolic pathway catalyzing the conversion of levodopa to 3-O-methyldopa (3-OMD), a potentially harmful metabolite of levodopa. Entacapone is a reversible, specific and mainly peripherally acting COMT inhibitor designed for concomitant administration with levodopa. Entacapone slows the clearance of levodopa from the bloodstream resulting in an increased area under the curve (AUC) in the pharmacokinetic profile of levodopa. Consequently the clinical response to each dose of levodopa is enhanced and prolonged.
The evidence of the therapeutic effects of Stalevo is based on two phase III double-blind studies, in which 376 Parkinson's disease patients with end-of-dose motor fluctuations received either entacapone or placebo with each levodopa/DDC inhibitor dose. Daily ON time with and without entacapone was recorded in home-diaries by patients. In the first study, entacapone increased the mean daily ON time by 1 h 20 min (CI 95% 45 min, 1 h 56 min) from baseline. This corresponded to an 8.3% increase in the proportion of daily ON time. Correspondingly, the decrease in daily OFF time was 24% in the entacapone group and 0% in the placebo group. In the second study, the mean proportion of daily ON time increased by 4.5% (CI95% 0.93%, 7.97%) from baseline. This is translated to a mean increase of 35 min in the daily ON time. Correspondingly, the daily OFF time decreased by 18% on entacapone and by 5% on placebo. Because the effects of Stalevo tablets are equivalent with entacapone 200 mg tablet administered concomitantly with the commercially available standard release carbidopa/levodopa preparations in corresponding doses these results are applicable to describe the effects of Stalevo as well.
General characteristics of the active substances
Absorption/Distribution: There are substantial inter- and intra-individual variations in the absorption of levodopa, carbidopa and entacapone. Both levodopa and entacapone are rapidly absorbed and eliminated. Carbidopa is absorbed and eliminated slightly slower compared with levodopa. When given separately without the two other active substances, the bioavailability for levodopa is 15-33%, for carbidopa 40-70% and for entacapone 35% after a 200 mg oral dose. Meals rich in large neutral amino acids may delay and reduce the absorption of levodopa. Food does not significantly affect the absorption of entacapone. The distribution volume of both levodopa (Vd 0.36-1.6 l/kg) and entacapone (Vdss 0.27 l/kg) is moderately small while no data for carbidopa are available.
Levodopa is bound to plasma protein only to a minor extent of about 10-30% and carbidopa is bound approximately 36%, while entacapone is extensively bound to plasma proteins (about 98%) –mainly to serum albumin. At therapeutic concentrations, entacapone does not displace other extensively bound active substances (e.g. warfarin, salicylic acid, phenylbutazone, or diazepam), nor is it displaced to any significant extent by any of these substances at therapeutic or higher concentrations.
Metabolism and Elimination: Levodopa is extensively metabolised to various metabolites: decarboxylation by dopa decarboxylase (DDC) and O-methylation by catechol-O-methyltransferase (COMT) being the most important pathways.
Carbidopa is metabolized to two main metabolites which are excreted in the urine as glucuronides and unconjugated compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.
Entacapone is almost completely metabolized prior to excretion via urine (10 to 20%) and bile/faeces (80 to 90%). The main metabolic pathway is glucuronidation of entacapone and its active metabolite, the cis-isomer, which accounts for about 5% of plasma total amount.
Total clearance for levodopa is in the range of 0.55-1.38 l/kg/h and for entacapone is in the range of 0.70 l/kg/h. The elimination-half life is (t1/2) is 0.6-1.3 hours for levodopa, 2-3 hours for carbidopa and 0.4-0.7 hours for entacapone, each given separately.
Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs on repeated administration.
Data from in vitro studies using human liver microsomal preparations indicate that entacapone inhibits cytochrome P450 2C9 (IC50 ~ 4 µM). Entacapone showed little or no inhibition of other types of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19); see section 4.5.
Characteristics in patients
Elderly: When given without carbidopa and entacapone, the absorption of levodopa is greater and elimination is slower in elderly than in young subjects. However, after combination of carbidopa with levodopa, the absorption of levodopa is similar between the elderly and the young, but the AUC is still 1.5 fold greater in the elderly due to decreased DDC activity and lower clearance by aging. There are no significant differences in the AUC of carbidopa or entacapone between younger (45–64 years) and elderly subjects (65–75 years).
Gender: Bioavailability of levodopa is significantly higher in women than in men. In the pharmacokinetic studies with Stalevo the bioavailability of levodopa is higher in women than in men, primarily due to the difference in body weight, while there is no gender difference with carbidopa and entacapone.
Hepatic impairment: The metabolism of entacapone is slowed in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) leading to an increased plasma concentration of entacapone both in the absorption and elimination phases (see sections 4.2 and 4.3). No particular studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment are reported, however, it is advised that Stalevo should be administered cautiously to patients with mild or moderate hepatic impairment.
Renal impairment: Renal impairment does not affect the pharmacokinetics of entacapone. No particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with renal impairment. However, a longer dosing interval of Stalevo may be considered for patients who are receiving dialysis therapy (see section 4.2).
Preclinical data of levodopa, carbidopa and entacapone, tested alone or in combination, revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. In repeated dose toxicity studies with entacapone, anaemia most likely due to iron chelating properties of entacapone was observed. Regarding reproduction toxicity of entacapone, decreased foetal weight and a slightly delayed bone development were noticed in rabbits treated at systemic exposure levels in the therapeutic range. Both levodopa and combinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits.
Tablet core:
Croscarmellose sodium
Magnesium stearate
Maize starch
Mannitol (E421)
Povidone (E1201)
Film-coating:
Glycerol (85 per cent) (E422)
Hypromellose
Magnesium stearate
Polysorbate 80
Red iron oxide (E172)
Sucrose
Titanium dioxide (E171)
Yellow iron oxide (E172)
Not applicable.
3 years.
This medicinal product does not require any special storage conditions.
HDPE bottle with a child resistant PP-closure.
Pack sizes:
10, 30, 100, 130, 175 and 250 tablets.
Not all pack sizes may be marketed.
Any unused product or waste material should be disposed of in accordance with local requirements.
Orion Corporation
Orionintie 1
FI-02200 Espoo
Finland
EU/1/03/260/001-004
EU/1/03/260/013
EU/1/03/260/016
Date of first authorisation: 17 October 2003
Date of last renewal: 15 September 2008
26 August 2010
Detailed information on this medicine is available on the European Medicine's Agency (EMA) web site: http://www.ema.europa.eu
