Erythromycin Tablets

ERYTHROMYCIN

Film-coated Tablets

Erythromycin Tablets, USP

Rx only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Erythromycin Base Film- coated tablets and other antibacterial drugs, Erythromycin Base Film-coated tablets would be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Erythromycin Tablets Description

Erythromycin Base Film-coated (Erythromycin Tablets, USP) is an antibacterial product containing erythromycin, USP, in a unique, nonenteric film coating for oral administration. Erythromycin Base Film-coated tablets are available in two strengths containing either 250 mg or 500 mg of erythromycin base.

Erythromycin is produced by a strain of Saccharopolyspora erythraea (formerly Streptomyces erythraeus) and belongs to the macrolide group of antibiotics. It is basic and readily forms salts with acids. Erythromycin is a white to off-white powder, slightly soluble in water, and soluble in alcohol, chloroform, and ether. Erythromycin is known chemically as (3R*, 4S*, 5S*, 6R*, 7R*, 9R*, 11R*, 12R*, 13S*, 14R*)-4-[(2,6-dideoxy-3-C-methyl-3-O - methyl - α - L - ribo - hexopyranosyl)oxy] - 14 - ethyl - 7,12,13 - trihydroxy - 3,5,7,9,11,13 - hexamethyl - 6 - [[3,4,6 - trideoxy - 3 - ( dimethylamino)- β - D - xylo-hexopyranosyl]oxy]oxacyclotetradecane-2,10-dione. The molecular formula is C37H67NO13, and the molecular weight is 733.94. The structural formula is:

Inactive Ingredients

Colloidal silicon dioxide, croscarmellose sodium, crospovidone, D&C Red No. 30 Aluminum Lake, hydroxypropyl cellulose, hypromellose, hydroxypropyl methylcellulose phthalate, magnesium stearate, microcrystalline cellulose, povidone, polyethylene glycol, propylene glycol, sodium citrate, sodium hydroxide, sorbic acid, sorbitan monooleate, talc, and titanium dioxide.

Erythromycin Tablets - Clinical Pharmacology

Orally administered erythromycin base and its salts are readily absorbed in the microbiologically active form. Interindividual variations in the absorption of erythromycin are, however, observed, and some patients do not achieve optimal serum levels. Erythromycin is largely bound to plasma proteins. After absorption, erythromycin diffuses readily into most body fluids. In the absence of meningeal inflammation, low concentrations are normally achieved in the spinal fluid but the passage of the drug across the blood-brain barrier increases in meningitis. Erythromycin crosses the placental barrier, but fetal plasma levels are low. The drug is excreted in human milk. Erythromycin is not removed by peritoneal dialysis or hemodialysis.

In the presence of normal hepatic function, erythromycin is concentrated in the liver and is excreted in the bile; the effect of hepatic dysfunction on biliary excretion of erythromycin is not known. After oral administration, less than 5% of the administered dose can be recovered in the active form in the urine.

Optimal blood levels are obtained when Erythromycin Base Film-coated tablets are given in the fasting state (at least 1/2 hour and preferably 2 hours before meals). Bioavailability data are available from Arbor Pharmaceuticals.

Microbiology

Erythromycin acts by inhibition of protein synthesis by binding 50 S ribosomal subunits of susceptible organisms. It does not affect nucleic acid synthesis. Antagonism has been demonstrated in vitro between erythromycin and clindamycin, lincomycin, and chloramphenicol.

Many strains of Haemophilus influenzae are resistant to erythromycin alone but are susceptible to erythromycin and sulfonamides used concomitantly.

Staphylococci resistant to erythromycin may emerge during a course of erythromycin therapy.

Erythromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive organisms:

 

Corynebacterium diphtheriae

 

Corynebacterium minutissimum

 

Listeria monocytogenes

 

Staphylococcus aureus (resistant organisms may emerge during treatment)

 

Streptococcus pneumoniae

 

Streptococcus pyogenes

Gram-negative organisms:

 

Bordetella pertussis

 

Legionella pneumophila

 

Neisseria gonorrhoeae

Other microorganisms:

 

Chlamydia trachomatis

 

Entamoeba histolytica

 

Mycoplasma pneumoniae

 

Treponema pallidum

 

Ureaplasma urealyticum

The following in vitro data are available, but their clinical significance is unknown.

Erythromycin exhibits in vitro minimal inhibitory concentrations (MIC 's) of 0.5 µg/mL or less against most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of erythromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-positive organisms:

 

Viridans group streptococci

Gram-negative organisms:

 

Moraxella catarrhalis

Susceptibility Tests

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC 's). These MIC 's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC 's should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of erythromycin powder. The MIC values should be interpreted according to the following criteria:

MIC (µg/mL )	Interpretation
≤0.5	Susceptible (S)
1-4	Intermediate (I)
≥8	Resistant (R)

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard erythromycin powder should provide the following MIC values:

Microorganism	MIC (µg/mL)
S. aureus ATCC 29213	0.12-0.5
E. faecalis ATCC 29212	1-4

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-µg erythromycin to test the susceptibility of microorganisms to erythromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15-µg erythromycin disk should be interpreted according to the following criteria:

Zone Diameter (mm)	Interpretation
≥23	Susceptible (S)
14-22	Intermediate (I)
≤13	Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for erythromycin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15-µg erythromycin disk should provide the following zone diameters in these laboratory test quality control strains:

Microorganism	Zone Diameter (mm)
S. aureus ATCC 25923	22-30

Indications and Usage for Erythromycin Tablets

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Erythromycin Base Film-coated tablets and other antibacterial drugs, Erythromycin Base Film-coated tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Erythromycin Base Film-coated tablets are indicated in the treatment of infections caused by susceptible strains of the designated microorganisms in the diseases listed below:

Upper respiratory tract infections of mild to moderate degree caused by Streptococcus pyogenes; Streptococcus pneumoniae; Haemophilus influenzae (when used concomitantly with adequate doses of sulfonamides, since many strains of H. influenzae are not susceptible to the erythromycin concentrations ordinarily achieved). (See appropriate sulfonamide labeling for prescribing information.)

Lower respiratory tract infections of mild to moderate severity caused by Streptococcus pyogenes or Streptococcus pneumoniae

Listeriosis caused by Listeria monocytogenes.

Respiratory tract infections due to Mycoplasma pneumoniae

Skin and skin structure infections of mild to moderate severity caused by Streptococcus pyogenes or Staphylococcus aureus (resistant staphylococci may emerge during treatment).

Pertussis (whooping cough) caused by Bordetella pertussis. Erythromycin is effective in eliminating the organism from the nasopharynx of infected individuals, rendering them noninfectious. Some clinical studies suggest that erythromycin may be helpful in the prophylaxis of pertussis in exposed susceptible individuals.

Diphtheria: Infections due to Corynebacterium diphtheriae, as an adjunct to antitoxin, to prevent establishment of carriers and to eradicate the organism in carriers.

Erythrasma: In the treatment of infections due to Corynebacterium minutissimum.

Intestinal amebiasis caused by Entamoeba histolytica (oral erythromycins only). Extraenteric amebiasis requires treatment with other agents.

Acute pelvic inflammatory disease caused by Neisseria gonorrhoeae: Erythrocin® Lactobionate-I. V. (erythromycin lactobionate for injection, USP ) followed by erythromycin base orally, as an alternative drug in treatment of acute pelvic inflammatory disease caused by N. gonorrhoeaein female patients with a history of sensitivity to penicillin. Patients should have a serologic test for syphilis before receiving erythromycin as treatment of gonorrhea and a follow-up serologic test for syphilis after 3 months.

Erythromycins are indicated for treatment of the following infections caused by Chlamydia trachomatis: conjunctivitis of the newborn, pneumonia of infancy, and urogenital infections during pregnancy. When tetracyclines are contraindicated or not tolerated, erythromycin is indicated for the treatment of uncomplicated urethral, endocervical, or rectal infections in adults due to Chlamydia trachomatis.3

When tetracyclines are contraindicated or not tolerated, erythromycin is indicated for the treatment of nongonococcal urethritis caused by Ureaplasma urealyticum.3

Primary syphilis caused by Treponema pallidum. Erythromycin (oral forms only) is an alternative choice of treatment for primary syphilis in patients allergic to the penicillins. In treatment of primary syphilis, spinal fluid should be examined before treatment and as part of the follow-up after therapy.

Legionnaires' Disease caused by Legionella pneumophila. Although no controlled clinical efficacy studies have been conducted, in vitro and limited preliminary clinical data suggest that erythromycin may be effective in treating Legionnaires' Disease.

Prophylaxis

Prevention of Initial Attacks of Rheumatic Fever

Penicillin is considered by the American Heart Association to be the drug of choice in the prevention of initial attacks of rheumatic fever (treatment of Streptococcus pyogenes infections of the upper respiratory tract e.g., tonsillitis, or pharyngitis).3 Erythromycin is indicated for the treatment of penicillin-allergic patients. The therapeutic dose should be administered for ten days.

Prevention of Recurrent Attacks of Rheumatic Fever

Penicillin or sulfonamides are considered by the American Heart Association to be the drugs of choice in the prevention of recurrent attacks of rheumatic fever. In patients who are allergic to penicillin and sulfonamides, oral erythromycin is recommended by the American Heart Association in the long-term prophylaxis of streptococcal pharyngitis (for the prevention of recurrent attacks of rheumatic fever).3

Contraindications

Erythromycin is contraindicated in patients with known hypersensitivity to this antibiotic.

Erythromycin is contraindicated in patients taking terfenadine, astemizole, or pimozide. (See PRECAUTIONS - Drug Interactions.)

Warnings

There have been reports of hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, occurring in patients receiving oral erythromycin products.

There have been reports suggesting that erythromycin does not reach the fetus in adequate concentration to prevent congenital syphilis. Infants born to women treated during pregnancy with oral erythromycin for early syphilis should be treated with an appropriate penicillin regimen.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ERYTHROMYCIN Base Film-coated tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin. Therefore, patients receiving concomitant lovastatin and erythromycin should be carefully monitored for creatine kinase (CK) and serum transaminase levels. (See package insert for lovastatin.)

Precautions

General

Prescribing Erythromycin Base Film-coated tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Since erythromycin is principally excreted by the liver, caution should be exercised when erythromycin is administered to patients with impaired hepatic function. (See CLINICAL PHARMACOLOGY and WARNINGS.)

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome have been reported in patients receiving erythromycin therapy.

There have been reports of infantile hypertrophic pyloric stenosis (IHPS) occurring in infants following erythromycin therapy. In one cohort of 157 newborns who were given erythromycin for pertussis prophylaxis, seven neonates (5%) developed symptoms of non-bilious vomiting or irritability with feeding and were subsequently diagnosed as having IHPS requiring surgical pyloromyotomy. A possible dose-response effect was described with an absolute risk of IHPS of 5.1% for infants who took erythromycin for 8-14 days and 10% for infants who took erythromycin for 15-21 days.4 Since erythromycin may be used in the treatment of conditions in infants which are associated with significant mortality or morbidity (such as pertussis or neonatal Chlamydia trachomatis infections), the benefit of erythromycin therapy needs to be weighed against the potential risk of developing IHPS. Parents should be informed to contact their physician if vomiting or irritability with feeding occurs.

Prolonged or repeated use of erythromycin may result in an overgrowth of nonsusceptible bacteria or fungi. If superinfection occurs, erythromycin should be discontinued and appropriate therapy instituted.

When indicated, incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy.

Information for Patients

Patients should be counseled that antibacterial drugs including Erythromycin Base Film-coated tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Erythromycin Base Film-coated tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Erythromycin Base Film-coated tablets or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase in serum theophylline levels and potential theophylline toxicity. In case of theophylline toxicity and/or elevated serum theophylline levels, the dose of theophylline should be reduced while the patient is receiving concomitant erythromycin therapy.

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, belonging to the calcium channel blockers drug class.

Concomitant administration of erythromycin and digoxin has been reported to result in elevated digoxin serum levels.

There have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants were used concomitantly. Increased anticoagulation effects due to interactions of erythromycin with oral anticoagulants may be more pronounced in the elderly.

Erythromycin is a substrate and inhibitor of the 3A isoform subfamily of the cytochrome p450 enzyme system (CYP3A). Coadministration of erythromycin and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both the therapeutic and adverse effects of the concomitant drug. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving erythromycin.

The following are examples of some clinically significant CYP3A based drug interactions. Interactions with other drugs metabolized by the CYP3A isoform are also possible. The following CYP3A based drug interactions have been observed with erythromycin products in post-marketing experience:

Ergotamine/dihydroergotamine

Concurrent use of erythromycin and ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.

Triazolobenzodiazepines (such as triazolam and alprazolam) and Related Benzodiazepines

Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.

HMG-CoA Reductase Inhibitors

Erythromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g., lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.

Sildenafil (Viagra)

Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. Reduction of sildenafil dosage should be considered. (See Viagra package insert.)

There have been spontaneous or published reports of CYP3A based interactions of erythromycin with cyclosporine, carbamazepine, tacrolimus, alfentanil, disopyramide, rifabutin, quinidine, methylprednisolone, cilostazol, vinblastine, and bromocriptine.

Concomitant administration of erythromycin with cisapride, pimozide, astemizole, or terfenadine is contraindicated. (See CONTRAINDICATIONS.)

In addition, there have been reports of interactions of erythromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.

Erythromycin has been reported to significantly alter the metabolism of the nonsedating antihistamines terfenadine and astemizole when taken concomitantly. Rare cases of serious cardiovascular adverse events, including electrocardiographic QT/QT c interval prolongation, cardiac arrest, torsades de pointes, and other ventricular arrhythmias, have been observed. (See CONTRAINDICATIONS.) In addition, deaths have been reported rarely with concomitant administration of terfenadine and erythromycin.

There have been post-marketing reports of drug interactions when erythromycin was co-administered with cisapride, resulting in QT prolongation, cardiac arrhythmias, ventricular tachycardia, ventricular fibrillation, and torsades de pointes, most likely due to the inhibition of hepatic metabolism of cisapride by erythromycin. Fatalities have been reported. (See CONTRAINDICATIONS).

Drug/Laboratory Test Interactions

Erythromycin interferes with the fluorometric determination of urinary catecholamines.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term (2-year) oral studies conducted in rats with erythromycin base did not provide evidence of tumorigenicity. Mutagenicity studies have not been conducted. There was no apparent effect on male or female fertility in rats fed erythromycin (base) at levels up to 0.25 percent of diet.

Pregnancy

Teratogenic effects

Pregnancy Category B

There is no evidence of teratogenicity or any other adverse effect on reproduction in female rats fed erythromycin base (up to 0.25 percent of diet) prior to and during mating, during gestation, and through weaning of two successive litters. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

The effect of erythromycin on labor and delivery is unknown.

Nursing Mothers

Erythromycin is excreted in human milk. Caution should be exercised when erythromycin is administered to a nursing woman.

Pediatric Use

See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.

Geriatric Use

Elderly patients, particularly those with reduced renal or hepatic function, may be at increased risk for developing erythromycin-induced hearing loss. (See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Elderly patients may be more susceptible to the development of torsades de pointes arrhythmias than younger patients. (See ADVERSE REACTIONS).

Elderly patients may experience increased effects of oral anticoagulant therapy while undergoing treatment with erythromycin. (See PRECAUTIONS - Drug Interactions).

Erythromycin Base Film-coated Tablets (250 mg) contain 8.5 mg (0.4 mEq) of sodium per tablet.

Erythromycin Base Film-coated Tablets (500 mg) contain 17.0 mg (0.7 mEq) of sodium per tablet.

The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.

Adverse Reactions

The most frequent side effects of oral erythromycin preparations are gastrointestinal and are dose-related. They include nausea, vomiting, abdominal pain, diarrhea and anorexia. Symptoms of hepatitis, hepatic dysfunction and/or abnormal liver function test results may occur. (See WARNINGS.)

Onset of pseudomembranou scolitis symptoms may occur during or after antibacteria l treatment. (See WARNINGS.)

Erythromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes.

Allergic reactions ranging from urticaria to anaphylaxis have occurred. Skin reactions ranging from mild eruptions to erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely.

There have been rare reports of pancreatitis and convulsions.

There have been isolated reports of reversible hearing loss occurring chiefly in patients with renal insufficiency and in patients receiving high doses of erythromycin.

Overdosage

In case of overdosage, erythromycin should be discontinued. Overdosage should be handled with the prompt elimination of unabsorbed drug and all other appropriate measures should be instituted.

Erythromycin is not removed by peritoneal dialysis or hemodialysis.

Erythromycin Tablets Dosage and Administration

Optimal blood levels are obtained when Erythromycin Base Film-coated tablets are given in the fasting state (at least 1/2 hour and preferably 2 hours before meals).

Adults

The usual dosage of Erythromycin Base Film-coated is one 250 mg tablet four times daily in equally spaced doses or one 500 mg tablet every 12 hours. Dosage may be increased up to 4 g per day according to the severity of the infection. However, twice-a-day dosing is not recommended when doses larger than 1 g daily are administered.

Children

Age, weight, and severity of the infection are important factors in determining the proper dosage. The usual dosage is 30 to 50 mg/kg/day, in equally divided doses. For more severe infections this dosage may be doubled but should not exceed 4 g per day.

In the treatment of streptococcal infections of the upper respiratory tract (e.g., tonsillitis or pharyngitis), the therapeutic dosage of erythromycin should be administered for at least ten days.

The American Heart Association suggests a dosage of 250 mg of erythromycin orally, twice a day in long-term prophylaxis of streptococcal upper respiratory tract infections for the prevention of recurring attacks of rheumatic fever in patients allergic to penicillin and sulfonamides.3

Conjunctivitis of the Newborn Caused by Chlamydia trachomatis

Oral erythromycin suspension 50 mg/kg/day in 4 divided doses for at least 2 weeks.3

Pneumonia of Infancy Caused by Chlamydia trachomatis

Although the optimal duration of therapy has not been established, the recommended therapy is oral erythromycin suspension 50 mg/kg/day in 4 divided doses for at least 3 weeks.

Urogenital Infections During Pregnancy Due to Chlamydia trachomatis

Although the optimal dose and duration of therapy have not been established, the suggested treatment is 500 mg of erythromycin by mouth four times a day on an empty stomach for at least 7 days. For women who cannot tolerate this regimen, a decreased dose of one erythromycin 500 mg tablet orally every 12 hours or 250 mg by mouth four times a day should be used for at least 14 days.5

For adults with uncomplicated urethral, endocervical, or rectal infections caused by Chlamydia trachomatis, when tetracycline is contraindicated or not tolerated: 500 mg of erythromycin by mouth four times a day for at least 7 days.5

For patients with nongonococcal urethritis caused by Ureaplasma urealyticum when tetracycline is contraindicated or not tolerated: 500 mg of erythromycin by mouth four times a day for at least seven days.5

Primary syphilis

30 to 40 g given in divided doses over a period of 10 to 15 days.

Acute Pelvic Inflammatory Disease Caused by N. gonorrhoeae

500 mg Erythrocin® Lactobionate-I.V. (erythromycin lactobionate for injection, USP) every 6 hours for 3 days, followed by 500 mg of erythromycin base orally every 12 hours for 7 days.

Intestinal Amebiasis

Adults

500 mg every 12 hours or 250 mg every 6 hours for 10 to 14 days.

Children

30 to 50 mg/kg/day in divided doses for 10 to 14 days.

Pertussis

Although optimal dosage and durationa hve not been established, doses of erythromycin utilized in reported clinical studies were 40 to 50 mg/kg/day, given in divided doses for 5 to 14 days.

Legionnaires' Disease

Although optimal dosage has not been established, doses utilized in reported clinical data were 1 to 4 g daily in divided doses.

How is Erythromycin Tablets Supplied

Erythromycin Base Film-coated tablets (Erythromycin Tablets, USP) are supplied as pink, unscored oval tablets in the following strengths and packages.

250 mg tablets (debossed with

Bottles of 100          (NDC 24338-102-13)

500 mg tablets (debossed with

Bottles of 100         ( NDC 24338-104-13).

The

Recommended Storage

Store below 86°F (30°C). Keep tightly closed.

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25 NCCLS, Villanova, PA, December 1993.


2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests, Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24 NCCL S, Villanova, PA, December 1993.


3. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, the American Heart Association: Prevention of Rheumatic Fever. Circulation. 78(4):1082-1086, October 1988.


4. Honein, M.A., et. al.: Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromycin: a case review and cohort study. The Lancet 1999; 354 (9196): 2101-5.


5. Data on file, Arbor Pharmaceuticals, Inc.

03-A424-R1

Revised: February, 2011

Arbor Pharmaceuticals, Inc.

Raleigh, NC 27606 USA

(Nos. 6326 and 6227)

PRINCIPAL DISPLAY PANEL - 250 mg Bottle Label

NDC 24338-102-13

100 Tablets

ERYTHROMYCIN

Base Film-Coated Tablets

ERYTHROMYCIN

TABLETS, USP

250 mg

Erythromycin,

USP

Tablet identification code format

change adopted October, 2000.

Rx only

arbor™

PHARMACEUTICALS, INC.

www.arborpharma.com

PRINCIPAL DISPLAY PANEL - 500 mg Bottle Label

NDC 24338-104-13

100 Tablets

ERYTHROMYCIN

Base Film-Coated Tablets

ERYTHROMYCIN

TABLETS, USP

500 mg

Erythromycin,

USP

Tablet identification code format

change adopted October, 2000.

Rx only

arbor™

PHARMACEUTICALS, INC.

www.arborpharma.com

ERYTHROMYCIN   BASE erythromycin  tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 24338-102 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Erythromycin (Erythromycin) Erythromycin 250 mg

Inactive Ingredients Ingredient Name Strength Silicon Dioxide   croscarmellose sodium   crospovidone   D&C Red No. 30   aluminum oxide   hydroxypropyl cellulose   hypromelloses   cellulose, microcrystalline   povidone   polyethylene glycols   propylene glycol   sodium citrate   sodium hydroxide   sorbic acid   sorbitan monooleate   talc   titanium dioxide

Product Characteristics Color PINK Score no score Shape OVAL Size 15mm Flavor Imprint Code EB Contains

Packaging # NDC Package Description Multilevel Packaging 1 24338-102-13 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA061621	09/06/2011

ERYTHROMYCIN   BASE erythromycin  tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 24338-104 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Erythromycin (Erythromycin) Erythromycin 500 mg

Inactive Ingredients Ingredient Name Strength Silicon Dioxide   croscarmellose sodium   crospovidone   D&C Red No. 30   aluminum oxide   hydroxypropyl cellulose   hypromelloses   cellulose, microcrystalline   povidone   polyethylene glycols   propylene glycol   sodium citrate   sodium hydroxide   sorbic acid   sorbitan monooleate   talc   titanium dioxide

Product Characteristics Color PINK Score no score Shape OVAL Size 19mm Flavor Imprint Code EA Contains

Packaging # NDC Package Description Multilevel Packaging 1 24338-104-13 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA061621	09/06/2011

Labeler - Arbor Pharmaceuticals, Inc. (781796417)

Revised: 12/2011Arbor Pharmaceuticals, Inc.

Boots Dual Action Athlete's Foot Spray

1. Name Of The Medicinal Product

Dual Action Athlete's Foot Spray

2. Qualitative And Quantitative Composition

Active Ingredient	% quantity
Tolnaftate	0.12 w/w

3. Pharmaceutical Form

Dry Powder Spray

4. Clinical Particulars

4.1 Therapeutic Indications

The product is indicated for the adjunctive treatment and prevention of athlete's foot (tinea pedis). It may also be helpful in conditions where tenderness and sweating cause skin irritation. It is also effective in other conditions, such as dhobie itch (tinea cruris) and prickly heat (miliaria).

4.2 Posology And Method Of Administration

Adults, elderly and children over 2 Years

The affected area should be treated morning and night.

Treatment should continue for at least a week after the infection has cleared up.

Children under 2 Years

Not recommended except under the advice and supervision of a doctor

For topical application to the skin.

4.3 Contraindications

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

If irritation or hypersensitivity occurs or if the condition does not improve within 10 days or becomes worse, treatment should be discontinued and medical advice sought.

Avoid contact with eyes.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant drug interactions known.

4.6 Pregnancy And Lactation

Safety in pregnancy has not been established. However, no teratogenic effects have been observed in clinical use. In studies in rats and mice, tolnaftate did not exert a deleterious effect on foetal or postnatal development.

If is not known whether topical tolnaftate is secreted into breast milk. However no undesirable effects in breast fed infants whose mothers were using tolnaftate have been reported.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

Skin reactions occur rarely and may include irritation and contact dermatitis.

4.9 Overdose

Not applicable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Tolnaftate is an established antifungal agent which appears to produce its effects through inhibition of sterol synthesis.

5.2 Pharmacokinetic Properties

No data available.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Talc extra 5/0 - M20 DEC

Denatured ethanol B grade

Disteardimonium hectorite

Dimethyl ether

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Store below 25°C.

Caution: Flammable.

Pressurised container, protect from sunlight and do not expose to temperatures exceeding 50°C.

Do not pierce or burn, even after use.

Do not spray on a naked flame or any incandescent material.

Avoid inhalation.

Do not use near, or place container on, polished or painted surfaces. CFC-Free - does not contain CFC's which damage ozone.

6.5 Nature And Contents Of Container

Internally lacquered aluminium can fitted with a continuous spray valve and an actuator.

Pack size: 150 millilitres

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham NG2 3AA

8. Marketing Authorisation Number(S)

PL 00014/0520

9. Date Of First Authorisation/Renewal Of The Authorisation

26 April 1996.

10. Date Of Revision Of The Text

June 2001.

Triapin Mite tablets

1. Name Of The Medicinal Product

Triapin mite 2.5mg/2.5mg prolonged release tablets

2. Qualitative And Quantitative Composition

Each tablet contains 2.5 mg of felodipine and 2.5 mg of ramipril.

Each tablet contains 52 mg lactose anhydrous.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Triapin mite 2.5mg/2.5mg tablets are circular (diameter approx 9 mm), apricot coloured, biconvex and engraved on one side and marked 2.5 on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of essential hypertension. Triapin mite fixed dose combination is indicated in patients whose blood pressure is not adequately controlled on felodipine or ramipril alone.

4.2 Posology And Method Of Administration

Posology

Use in adults, including elderly:

One tablet Triapin mite once daily. The maximum dose is two tablets Triapin mite once daily.

Special populations

Use in patients with impaired liver function:

See sections 4.3 and 4.4.

Use in patients with impaired renal function or patients already on diuretic treatment:

See sections 4.3 and 4.4.

Individual dose titration with the components can be recommended and when clinically appropriate, direct change from monotherapy to the fixed combination may be considered.

Paediatric population:

Triapin mite is not recommended for use in children due to a lack of data.

Method of administration

Triapin mite tablets should be swallowed whole with a sufficient amount of liquid. The tablets must not be divided, crushed or chewed. The tablet can be administered without food or following a light meal not rich in fat or carbohydrate.

4.3 Contraindications

Triapin Mite must not be used:

• in patients with hypersensitivity to felodipine (or other dihydropyridines), ramipril, other angiotensin converting enzyme (ACE) inhibitors or any of the excipients of Triapin mite.

• in patients with a history of angioedema.

• in unstable haemodynamic conditions: cardiovascular shock, untreated heart failure, acute myocardial infarction, unstable angina pectoris, stroke.

• in patients with AV block II or III.

• in patients with severely impaired hepatic function.

• in patients with severely impaired renal function (creatinine clearance less than 20 ml/min) and in patients on dialysis.

• during pregnancy.

• during lactation.

4.4 Special Warnings And Precautions For Use

Angioedema

Angioedema occurring during treatment with an ACE inhibitor necessitates immediate discontinuation of the medicinal product. Angioedema may involve the tongue, glottis or larynx and, if so, may necessitate emergency measures.

Angioedema of the face, extremities, lips, tongue, glottis or larynx has been reported in patients treated with ACE inhibitors. Emergency therapy should be given including, but not necessarily limited to, immediate subcutaneous adrenalin solution 1:1000 (0.3 to 0.5 ml) or slow intravenous adrenalin 1 mg/ml (observe dilution instructions) with control of ECG and blood pressure. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C1-esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Compared with non-black patients, a higher incidence of angioedema has been reported in black patients treated with ACE inhibitors.

Renal function

Renal function should be monitored, particularly in the initial weeks of treatment with ACE inhibitors. Caution should be observed in patients with an activated renin-angiotensin system.

Patients with mild to moderately impaired renal function (creatinine clearance 20-60 ml/min) and patients already on diuretic treatment: For dosage see the respective monoproducts.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including ramipril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or those patients taking other medicinal products associated with increases in serum potassium (e.g. heparin). If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended.

Proteinuria

It may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.

Renovascular hypertension/renal artery stenosis

There is an increased risk of severe hypotension and renal insufficiency when patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine even in patients with unilateral renal artery stenosis.

There is no experience regarding the administration of Triapin mite in patients with a recent kidney transplantation.

Hepatic failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progress to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Patients with mild to moderately impaired liver function

For dosage see respective monoproducts.

Surgery/Anaesthesia

Hypotension may occur in patients undergoing major surgery or during treatment with anaesthetic agents that are known to lower blood pressure. If hypotension occurs, it may be corrected by volume expansion.

Aortic stenosis/Hypertrophic cardiomyopathy

ACE inhibitors should be used with caution in patients with haemodynamically relevant left-ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve, obstructive cardiomyopathy). The initial phase of treatment requires special medical supervision.

Symptomatic hypotension

In some patients, symptomatic hypotension may be observed after the initial dose, mainly in patients with heart failure (with or without renal insufficiency) treated with high doses of loop diuretics, in hyponatraemia or in reduced renal function. Therefore, Triapin mite should only be given to such patients after special considerations and after the doses of the individual components have been carefully titrated. Triapin mite should only be given if the patient is in a stable circulatory condition (see section 4.3). In hypertensive patients without cardiac and renal insufficiency, hypotension may occur especially in patients with decreased blood volume due to diuretic therapy, salt restriction, diarrhoea or vomiting.

Patients who would be at particular risk from an undesirably pronounced reduction in blood pressure (e.g. patients with coronary or cerebrovascular insufficiency) should be treated with ramipril and felodipine in a free combination. If satisfactory and stable blood pressure control is achieved with the doses of ramipril and felodipine included in Triapin mite, the patient can be switched to this combination. In some cases, felodipine may cause hypotension with tachycardia, which may aggravate angina pectoris.

Neutropenia/Agranulocytosis

Triapin mite may cause agranulocytosis and neutropenia. These undesirable effects have also been shown with other ACE inhibitors, rarely in uncomplicated patients but more frequently in patients with some degree of renal impairment, especially when it is associated with collagen vascular disease (e.g. systemic lupus erythematodes, scleroderma) and therapy with immunosuppressive agents. Monitoring of white blood cell counts should be considered for patients who have collagen vascular disease, especially if the disease is associated with impaired renal function. Neutropenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Should symptoms such as fever, swelling of the lymph nodes, and/or inflammation of the throat occur in the course of therapy with Triapin mite, the treating physician must be consulted and the white blood picture investigated immediately.

Cough

During treatment with an ACE inhibitor a dry cough may occur which disappears after discontinuation.

Concomitant treatment with ACER inhibitors and antidiabetics

Concomitant treatment with ACE inhibitors and antidiabetics (insulin and oral antidiabetics) may lead to an enhanced hypoglycaemic effect with the risk of hypoglycaemia. This effect may be most pronounced at the beginning of treatment and in patients with impaired renal function.

Felodipine is metabolised by CYP3A4. Therefore, combination with medicinal products which are potent CYP3A4 inhibitors or inducers should be avoided. For the same reason, the concomitant intake of grapefruit juice should be avoided (see section 4.5).

Lithium

The combination of lithium and ACE inhibitors is not recommended. (see section 4.5).

LDL-apheresis

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces should be avoided since it may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-flux (e.g. polyacrylonitrile) membranes and low-density lipoprotein apheresis with dextran sulphate.

Desensitisation therapy

Increased likelihood and greater severity of anaphylactic and anaphylactoid reactions to insect venom (e.g. bee and wasp) as for other ACE inhibitors.

Ethnic differences

As with other angiotensin converting enzyme inhibitors, ramipril is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

Children, patients with creatinine clearance under 20 ml/min and dialysis-treated patients

No experience is available. Triapin mite should not be given to these patient groups.

Lactose

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not recommended associations

Potassium salts, potassium-retaining diuretics: Rise in serum potassium concentration is to be anticipated. Concomitant treatment with potassium-retaining diuretics (e.g. spironolactone, triamterene, or amiloride) or with potassium salts requires close monitoring of serum potassium.

Felodipine is a CYP3A4 substrate. Medicinal products that induce or inhibit CYP3A4 will have large influence on felodipine plasma concentrations.

Medicinal products that increase the metabolism of felodipine through induction of cytochrome P450 3A4 include carbamazepine, phenytoin, phenobarbital and rifampin as well as St John's wort (Hypericum perforatum). During concomitant administration of felodipine with carbamazepine, phenytoin, phenobarbital, AUC decreased by 93% and C_max by 82%. A similar effect is expected with St John's wort. Combination with CYP3A4 inducers should be avoided.

Potent inhibitors of cytochrome P450 3A4 include azole antifungals, macrolide antibiotics, telithomycin and HIV protease inhibitors. During concomitant administration of felodipine with itraconazole, C_max increased 8-fold and AUC 6-fold. During concomitant administration of felodipine with erythromycin, C_max and AUC increased approximately 2.5-fold. Combination with potent CYP3A4 inhibitors should be avoided.

Grapefruit juice inhibits cytochrome P450 3A4. Concomitant administration of felodipine with grapefruit juice increased felodipine C_max and AUC approximately 2-fold. The combination should be avoided.

Caution is recommended with concomitant use

Lithium

Excretion of lithium may be reduced by ACE inhibitors, leading to lithium toxicity. Lithium levels must, therefore, be monitored.

Antihypertensive agents and other substances with blood pressure lowering potential (e.g. nitrates, antipsychotics, narcotics, anaesthetics)

Potentiation of the antihypertensive effect of Triapin mite is to be anticipated.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood picture

Increased likelihood of haematological reactions.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Attenuation of the effect of ramipril is to be expected. Furthermore, concomitant treatment with ACE inhibitors and such medicinal products may lead to an increased risk of worsening of the renal function and an increase in serum potassium.

Vasopressor sympathomimetics

These may reduce the antihypertensive effect of Triapin mite. Particularly close blood pressure monitoring is recommended.

Insulins, metformin, sulphonylureas

Concomitant treatment with ACE inhibitors and antidiabetic agents may cause a pronounced hypoglycaemic effect with the risk of hypoglycaemia. This effect is most pronounced at the beginning of treatment.

Theophylline

Concomitant administration of felodipine and oral theophylline reduces theophylline absorption by approximately 20%. This is probably of minor clinical importance.

Tacrolimus

Felodipine may increase the concentration of tacrolimus. When used together, the tacrolimus serum concentration should be followed and the tacrolimus dose may need to be adjusted.

Heparin

Rise in serum potassium concentration possible.

Salt

Increased dietary salt intake may attenuate the antihypertensive effect of Triapin mite.

Alcohol

Increased vasodilatation. The antihypertensive effect of Triapin mite may increase.

4.6 Pregnancy And Lactation

Pregnancy

Triapin mite is contra-indicated (see section, 4.3.) in pregnancy.

Calcium antagonists may inhibit contractions of the uterus during labour. Definite evidence that labour is prolonged in full-term pregnancy is lacking. Risk of foetal hypoxia may occur if the mother is hypotensive and perfusion of the uterus is reduced due to redistribution of the blood-flow through peripheral vasodilatation. In animal experiments, calcium antagonists have caused embryotoxic and/or teratogenic effects, especially in the form of distal skeletal malformations in several species.

Appropriate and well-controlled studies with ramipril have not been done in humans. ACE inhibitors cross the placenta and can cause foetal and neonatal morbidity and mortality when administered to pregnant women.

Fetal exposure to ACE inhibitors during the second and third trimesters has been associated with neonatal hypotension, renal failure, face or skull deformities and/or death. Maternal oligohydramnios have also been reported reflecting decreasing renal function in the fetus. Limb contractures, craniofacial deformities, hypoplastic lung development and intrauterine growth retardation have been reported in association with oligohydramnios. Intrauterine growth retardation, prematurity, persistent ductus arteriosus and fetal death have also been reported, but it is not clear whether they are related to the ACE inhibitor or to the underlying maternal disease. Whether exposure limited to the first trimester can adversely effect fetal outcome is not known.

Breastfeeding

In animals, ramipril is excreted in milk. No information is available on whether or not ramipril is excreted in human breast-milk. Felodipine is excreted in human breast-milk.

Women must not breast-feed during treatment with Triapin mite (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

Some undesirable effects (e.g. some symptoms of reduction in blood pressure such as dizziness) may be accompanied by an impairment of the ability to concentrate and react. This may constitute a risk in situations where these abilities are of special importance, e.g., when driving a car or operating machinery.

4.8 Undesirable Effects

The frequencies used in the tables throughout this section are:

very common (

The following undesirable effects may occur in connection with felodipine treatment

Frequencies/Organ System	Common	Uncommon	Rare	Very rare
Immune system disorders				Hypersensitivity reactions
Metabolism and nutrition disorders				Hyperglycaemia
Psychiatric disorders			Impotence/sexual dysfunction
Nervous system disorders	Headache	Dizziness, paraesthesiae	Syncope
Cardiac Disorders		Tachycardia, palpitations
Vascular disorders	Flush, peripheral oedema			Leucocytoclastic vasculitis
Gastrointestinal Disorders		Nausea, abdominal pain	Vomiting	Gingival hyperplasia, gingivitis
Hepatobiliary disorders				Increased liver enzymes
Skin and Subcutaneous Tissue Disorders		Rash, pruritus	Urticaria	Photosensitivity reactions, angioedema
Musculoskeletal and Connective Tissue Disorders			Arthralgia, myalgia
Renal and urinary disorders				Pollakisuria
General Disorders and Administration Site conditions		Fatigue		Fever

The following undesirable effects may occur in connection with ramipril treatment

Frequencies/Organ System	Common	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system disorders		Eosinophilia	White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased		Bone marrow failure, pancytopenia, haemolytic anaemia
Immune system disorders					Anaphylactic or anaphylactoid reactions, antinuclear antibody increased
Metabolism and nutrition disorders	Blood potassium increased	Anorexia, decreased appetite			Blood sodium decreased
Psychiatric disorders		Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence	Confusional state		Disturbance in attention
Nervous system disorders	Headache, dizziness	Vertigo, paraesthesia, ageusia, dysgeusia	Tremor, balance disorder		Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia
Eye disorders		Visual disturbance including blurred vision	Conjunctivitis
Ear and labyrinth disorders			Hearing impaired, tinnitus
Cardiac Disorders		Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral
Vascular disorders	Hypotension orthostatic blood pressure decreased, syncope	Flushing	Vascular stenosis, hypoperfusion, vasculitis		Raynaud's phenomenon
Respiratory, thoracic and mediastinal disorders	Non-productive tickling cough, bronchitis, sinusitis, dyspnoea	Bronchospasm including asthma aggravated, nasal congestion
Gastrointestinal disorders	Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting	Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth	Glossitis		Aphtous stomatitis
Hepatobiliary disorders		Hepatic enzymes and/or bilirubin conjugated increased	Jaundice cholestatic, hepatocellular damage		Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).
Skin and subcutaneous disorders	Rash in particular maculo-papular	Angiodema; very exceptionally, airway obstruction resulting from angiodema may have a fatal outcome, pruritis, hyperhidrosis	Exfoliative dermatitis, urticaria, onycholysis	Photosensitivity reaction	Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme pemphigus, psoriasis aggravated, dermatitis psoriasisform, pemphigoid or lichenoid exanthema or enanthema, alopecia
Musculoskeletal and connective tissue disorders	Muscle spasms, myalgia	Arthralgia
Renal and urinary disorders		Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased
Reproductive system and breast disorders		Transient erectile impotence, libido decreased			Gynaecomastia
General disorders and administration site conditions	Chest pain, fatigue	Pyrexia	Asthenia

4.9 Overdose

Symptoms

Overdosage may cause excessive peripheral vasodilatation with marked hypotension, bradycardia, shock, electrolyte disturbances and renal failure.

Management

Primary detoxification by, for example, gastric lavage, administration of adsorbents and/or sodium sulphate (if possible during the first 30 minutes). In case of hypotension, administration of α₁-adrenergic sympathomimetics and angiotensin II must be considered in addition to volume and salt substitution. Bradycardia or extensive vagal reactions should be treated by administering atropine.

No experience is available concerning the efficacy of forced diuresis, alteration in urine pH, haemofiltration, or dialysis in speeding up the elimination of ramipril or ramiprilat. If dialysis or haemofiltration is nevertheless considered, see also under 4.4 Special Warnings and Special Precautions for use.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antihypertensive drugs. ATC code: C09B B05

Both the calcium antagonist felodipine and the ACE inhibitor ramipril reduce blood pressure by dilation of the peripheral blood vessels. Calcium antagonists dilate the arterial beds while ACE inhibitors dilate both arterial and venous beds. Vasodilatation and thereby reduction of blood pressure may lead to activation of the sympathetic nervous system and the renin-angiotensin system. Inhibition of ACE results in decreased plasma angiotensin II.

The onset of the antihypertensive effect of a single dose of Triapin mite is 1 to 2 hours. The maximum antihypertensive effect is achieved within 2 to 4 weeks and is maintained during long-term therapy. The blood pressure reduction is maintained throughout the 24-hour dosage interval. Morbidity and mortality data are not available.

Felodipine is a vascular selective calcium antagonist, which lowers arterial blood pressure by decreasing peripheral vascular resistance via a direct relaxant action on vascular smooth muscles. Due to its selectivity for smooth muscle in the arterioles, felodipine, in therapeutic doses, has no direct effect on cardiac contractility or conduction. The renal vascular resistance is decreased by felodipine. The normal glomerular filtration rate is not influenced. In patients with impaired renal function, the glomerular filtration rate may increase. Felodipine possesses a mild natriuretic/diuretic effect and fluid retention does not occur.

Ramipril is a prodrug which hydrolyses to the active metabolite ramiprilat, a potent and long-acting ACE (angiotensin converting enzyme) inhibitor. In plasma and tissue, ACE catalyses the conversion of angiotensin I to the vasoconstrictor angiotensin II and also the breakdown of the vasodilator bradykinin. The vasodilatation induced by the ACE inhibitor reduces blood pressure pre-load and after-load. Since angiotensin II also stimulates the release of aldosterone, ramiprilat reduces secretion of aldosterone. Ramipril reduces peripheral arterial resistance without major changes in renal plasma flow or glomerular filtration rate. In hypertensive patients, ramipril leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

5.2 Pharmacokinetic Properties

General characteristics of the active substances

Felodipine ER (extended-release formulation): The bioavailability is approximately 15% and is not influenced by concomitant intake of food. The peak plasma concentration is reached after 3 to 5 hours. Binding to plasma proteins is more than 99%. The distribution volume at steady state is 10 l/kg. The half-life for felodipine in the elimination phase is approximately 25 hours and steady state is reached after 5 days. There is no risk of accumulation during long-term treatment. Mean clearance is 1200 ml/min. Decreased clearance in elderly patients leads to higher plasma concentrations of felodipine. Age only partly explains the inter-individual variation in plasma concentration, however. Felodipine is metabolised in the liver and all identified metabolites are devoid of vasodilating properties. Approximately 70% of a given dose is excreted as metabolites in the urine and about 10% with the faeces. Less than 0.5% of the dose is excreted unchanged in the urine. Impaired renal function does not influence the plasma concentration of felodipine.

Ramipril: The pharmacokinetic parameters of ramiprilat are calculated after intravenous administration of ramipril. Ramipril is metabolised in the liver, and aside from the active metabolite ramiprilat, pharmacologically inactive metabolites have been identified. The formation of active ramiprilat may be decreased in patients with impaired liver function. The metabolites are excreted mainly via the kidneys. The bioavailability of ramiprilat is approximately 28% after oral administration of ramipril. After intravenous administration of 2.5 mg ramipril, approximately 53% of the dose is converted to ramiprilat. A maximum serum concentration of ramiprilat is achieved after 2 to 4 hours. Absorption and bioavailability are not influenced by concomitant intake of food. The protein binding of ramiprilat is approximately 55%. The distribution volume is approximately 500 litres. The effective half-life, after repeated daily dosage of 5 to 10 mg, is 13 to 17 hours. Steady-state is achieved after approximately 4 days. Renal clearance is 70 to 100 ml/min and total clearance is approximately 380 ml/min. Impaired renal function delays the elimination of ramiprilat and excretion in the urine is reduced.

Characteristics of the combination product

In Triapin mite the pharmacokinetics of ramipril, ramiprilat and felodipine are essentially unaltered compared to the monoproducts, felodipine ER tablets and ramipril tablets. Felodipine does not influence the ACE inhibition caused by ramiprilat. The fixed combination tablets are thus regarded as bioequivalent to the free combination.

5.3 Preclinical Safety Data

Repeated-dose toxicity studies performed with the combination in rats and monkeys did not demonstrate any synergistic effects.

Non-clinical data for felodipine and ramipril reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.

Reproduction toxicity

Felodipine: In investigations on fertility and general reproductive performance in rats, a prolongation of parturition resulting in difficult labour/increased foetal deaths and early postnatal deaths was observed. Reproduction toxicity studies in rabbits have shown a dose-related reversible enlargement of the mammary glands of the parent animals and dose-related digital anomalies in the foetuses.

Ramipril: Studies in rats, rabbits and monkeys did not disclose any teratogenic properties. Daily doses during pregnancy and lactation in rats produced irreversible renal pelvis dilatation in the offspring.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Cellulose microcrystalline

Hyprolose

Hypromellose

Iron oxides E172

Lactose anhydrous

Macrogol 6000

Macrogolglycerol hydroxystearate

Maize starch

Paraffin

Propyl gallate

Sodium aluminium silicate

Sodium stearyl fumarate

Titanium dioxide E 171

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Triapin mite: 2 years

6.4 Special Precautions For Storage

Do not store above 30°C.

6.5 Nature And Contents Of Container

PVC/PVDC blisters: 28 tablets

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0321

9. Date Of First Authorisation/Renewal Of The Authorisation

15^th April 2002

15^th January 2008

10. Date Of Revision Of The Text

31 August 2011

LEGAL STATUS

POM