Metronidazole Injection

Metronidazole Injection, USP

Rx only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Metronidazole Injection, USP and other antibacterial drugs, Metronidazole Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

WARNING

Metronidazole has been shown to be carcinogenic in mice and rats (see Precautions). Its use, therefore, should be reserved for the conditions described in the Indications and Usage section below.

Description

Metronidazole Injection, USP is a parenteral dosage form of the synthetic antibacterial agent 1-(β-hydroxyethyl)-2-methyl-5- nitroimidazole.

Metronidazole Injection, USP, in 100 mL single dose plastic container, is a sterile, nonpyrogenic, iso-osmotic, buffered solution of 500 mg Metronidazole, USP, 790 mg Sodium Chloride, USP, 47.6 mg Anhydrous Disodium Hydrogen Phosphate, USP and 22.9 mg Citric Acid Monohydrate, USP. Metronidazole Injection, USP has an osmolarity of 310 mOsmol/L (calc) and a pH of 5.5 (4.5 to 7.0). Each container contains 14 mEq of sodium.

The plastic container is fabricated from a specially formulated polyvinyl chloride plastic. Water can permeate from inside the container into the overwrap in amounts insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million. However, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

Clinical Pharmacology

Metronidazole is a synthetic antibacterial compound. Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms, with an average elimination half-life in healthy humans of eight hours.

The major route of elimination of metronidazole and its metabolites is via the urine (60 - 80% of the dose), with fecal excretion accounting for 6 - 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation (1-[β-hydroxyethyl]-2-hydroxymethyl- 5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid) and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m2.

Metronidazole is the major component appearing in the plasma, with lesser quantities of the 2-hydroxymethyl metabolite also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Both the parent compound and the metabolite possess in vitro bactericidal activity against most strains of anaerobic bacteria.

Metronidazole appears in cerebrospinal fluid, saliva and breast milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses..

Plasma concentrations of metronidazole are proportional to the administered dose. An eight-hour intravenous infusion of 100-4,000 mg of metronidazole in normal subjects showed a linear relationship between dose and peak plasma concentration.

In patients treated with intravenous metronidazole, using a dosage regimen of 15 mg/kg loading dose followed six hours later by 7.5 mg/kg every six hours; peak steady-state plasma concentrations of metronidazole averaged 25 mcg/mL with trough (minimum) concentrations averaging 18 mcg/mL.

Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. However, plasma clearance of metronidazole is decreased in patients with decreased liver function.

In one study newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole. The elimination half-life, measured during the first three days of life, was inversely related to gestational age. In infants whose gestational ages were between 28 and 40 weeks, the corresponding elimination half-lives ranged from 109 to 22.5 hours.

Microbiology: Metronidazole is active in vitro against most obligate anaerobes, but does not appear to possess any clinically relevant activity against facultative anaerobes or obligate aerobes. Against susceptible organisms, metronidazole is generally bactericidal at concentrations equal to or slightly higher than the minimal inhibitory concentrations. Metronidazole has been shown to have in vitro and clinical activity against the following organisms:

Anaerobic gram-negative bacilli, including:

Bacteroides species, including the Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)

Fusobacterium species

Anaerobic gram-positive bacilli, including:

Clostridium species and susceptible strains of Eubacterium

Anaerobic gram-positive cocci, including:

Peptococcus species

Peptostreptococcus species

Many nonspore-forming, gram-positive anaerobic rods are resistant to metronidazole

Susceptibility Tests:


Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to metronidazole; however, the rapid routine susceptibility testing of individual isolates of anaerobic bacteria is not always practical, and therapy may be started while awaiting these results.

Quantitative methods give the most accurate estimates of susceptibility to antibacterial drugs. A standardized agar dilution method and a broth microdilution method are recommended.1

Interpretive criteria for determining the susceptibility of an organism to metronidazole are:

* MIC values for agar or broth micro dilution are considered equivalent.
Dilution*
MIC (mcg/mL)	Interpretation
≤ 8	(S) Susceptible
16	(I) Intermediate
≥ 32	(R) Resistant

A bacterial isolate may be considered susceptible if the MIC value for metronidazole is not more than 8 mcg/mL. An organism with a metronidazole MIC of 16 mcg/mL is considered intermediate in susceptibility. An organism is considered resistant if the MIC is greater than 16 mcg/mL. The intermediate range was established because of the difficulty in reading endpoints and the clustering of MICs at or near breakpoint concentrations. Where data are available, the interpretive guidelines are based on pharmacokinetic data, population distributions of MICs, and studies of clinical efficacy. To achieve the best possible levels of a drug in abscesses and/or poorly perfused tissues, which are encountered commonly in these infections, maximum approved dosages of antimicrobial agents are recommended for therapy of anaerobic infections. When maximum dosages are used along with appropriate ancillary therapy, it is believed that organisms with susceptible endpoints are generally amenable to therapy, and those with intermediate endpoints may respond, but patient response should be carefully monitored. Ancillary therapy, such as drainage procedures and debridement, are of great importance for the proper management of anaerobic infections. A report of "resistant" from the laboratory indicates that the infecting organism is not likely to respond to therapy. Routine testing of metronidazole for management of C difficile-associated diarrhea is not recommended because correlation with clinical failures has not been established.1

Control strains are recommended for standardized susceptibility testing. Each time the test is performed, one or more control strains should be included.

A clinical laboratory test is considered under acceptable control if the results of the control strains are within the MIC ranges reported below. 2

For reference agar dilution testing, metronidazole MIC ranges associated with control strains are:

* ATTC is a registered trademark of the American Type Culture Collection
Control Strain	ATCC® number *	MIC range (mcg/mL)
Bacteroides fragilis	25285	0.25 - 1
Bacteroides thetaiotaomicron	2974	0.5 - 2
Clostridium Difficile	700057	0.125 – 0.5

 For broth microdilution testing, metronidazole MIC ranges associated with control strains are:

* ATTC is a registered trademark of the American Type Culture Collection
Control Strain	ATCC® number *	MIC range (mcg/mL)
Bacteroides fragilis	25285	0.25 - 2
Bacteroides thetaiotaomicron	2974	0.5 - 4
Eubacterium Lentum	43055	0.125 – 0.5

Indications and Usage

Treatment of Anaerobic Infections

Metronidazole Injection, USP is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with Metronidazole Injection, USP therapy. In a mixed aerobic and anaerobic infection, antibiotics appropriate for the treatment of the aerobic infection should be used in addition to Metronidazole Injection, USP.

Metronidazole Injection, USP is effective in Bacteroides fragilis infections resistant to clindamycin, chloramphenicol and penicillin.

Intra-Abdominal Infections, including peritonitis, intra-abdominal abscess and liver abscess, caused by Bacteroides species including the B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Clostridium species, Eubacterium species, Peptococcus species and Peptostreptococcus species.

Skin and Skin Structure Infections caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species and Fusobacterium species.

Gynecologic Infections, including endometritis, endomyometritis, tubo-ovarian abscess, and post-surgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptostreptococcus species and Fusobacterium species.

Bacterial Septicemia caused by Bacteroides species including the B. fragilis group and Clostridium species.

Bone and Joint Infections, as adjunctive therapy, caused by Bacteroides species including the B. fragilis group.

Central Nervous System (CNS) Infections, including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group.

Lower Respiratory Tract Infections, including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group.

Endocarditis caused by Bacteroides species including the B. fragilis group.

Prophylaxis:

The prophylactic administration of Metronidazole Injection, USP preoperatively, intraoperatively and postoperatively may reduce the incidence of postoperative infection in patients undergoing elective colorectal surgery, which is classified as contaminated or potentially contaminated.

Prophylactic use of Metronidazole Injection, USP should be discontinued within 12 hours after surgery. If there are signs of infection, specimens for cultures should be obtained for the identification of the causative organism(s) so that appropriate therapy may be given (see Dosage and Administration).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Metronidazole Injection, USP and other antibacterial drugs, Metronidazole Injection, USP 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.

Contraindications

Metronidazole Injection, USP is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.

Warnings

Central And Peripheral Nervous System Effects

Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole.

Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole.

CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Convulsive seizures have been reported in patients treated with metronidazole. Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy.

Precautions

General:

Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses below those usually recommended should be administered cautiously.

Administration of solutions containing sodium ions may result in sodium retention. Care should be taken when administering Metronidazole Injection, USP to patients receiving corticosteroids or to patients predisposed to edema.

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with Metronidazole Injection, USP and requires treatment with a candicidal agent.

Prescribing Metronidazole Injection, USP 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.

Laboratory Tests:

Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hemotologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy.

Drug Interactions:

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when Metronidazole Injection, USP is prescribed for patients on this type of anticoagulant therapy.

The simultaneous administration of drugs that induce microsomal liver enzyme activity, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.

The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.

Alcoholic beverages should not be consumed during metronidazole therapy because abdominal cramps, nausea, vomiting, headaches and flushing may occur.

Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks.

Drug/Laboratory Test Interactions:

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotine adenine dinucleotide (NAD+ ↔ NADH). Interference is due to the similarity in absorbance peaks of NADH (340nm) and metronidazole (322nm) at pH 7.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tumorigenicity in Rodents - Metronidazole has shown evidence of carcinogenic activity in studies involving chronic, oral administration in mice and rats, but similar studies in the hamster gave negative results. Also, metronidazole has shown mutagenic activity in a number of in vitro assay systems, but studies in mammals (in vivo) failed to demonstrate a potential for genetic damage.

Pregnancy: Teratogenic Effects

Pregnancy Category B

Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Reproduction studies have been performed in rats at doses up to five times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to metronidazole. Metronidazole administered intraperitoneally to pregnant mice at approximately the human dose caused fetotoxicity; administered orally to pregnant mice, no fetotoxicity was observed. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and because metronidazole is a carcinogen in rodents, these drugs should be used during pregnancy only if clearly needed.

Nursing Mothers

Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Metronidazole is secreted in breast milk in concentrations similar to those found in plasma.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Information for Patients

Patients should be counseled that antibacterial drugs including Metronidazole Injection, USP should only be used to treat bacterial infections. They do not treat viral infections ( e.g., the common cold). When Metronidazole Injection, USP is 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 Metronidazole Injection, USP or other antibacterial drugs in the future.

Adverse Reactions

The most serious adverse reactions reported in patients treated with Metronidazole Injection have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged oral administration of metronidazole, patients should be observed carefully if neurologic symptoms occur and a prompt evaluation made of the benefit/risk ratio of the continuation of therapy.

The following reactions have also been reported during treatment with Metronidazole Injection, USP.

Gastrointestinal: Nausea, vomiting, abdominal discomfort, diarrhea and an unpleasant metallic taste.

Hematopoietic: Reversible neutropenia (leukopenia).

Dermatologic: Erythematous rash and pruritus.

Central Nervous System: Encephalopathy, aseptic meningitis, optic neuropathy, headache, dizziness, syncope, ataxia, confusion and dysarthria.

Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, flushing, nasal congestion, dryness of the mouth (or vagina or vulva) and fever.

Local Reactions: Thrombophlebitis after intravenous infusion. This reaction can be minimized or avoided by avoiding prolonged use of indwelling intravenous catheters.

Other: Fever. Instances of darkened urine have also been reported, and this manifestation has been the subject of a special investigation. Although the pigment, which is probably responsible for this phenomenon, has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance.

The following adverse reactions have been reported during treatment with oral metronidazole:

Gastrointestinal: Nausea, sometimes accompanied by headache, anorexia and occasionally vomiting; diarrhea, epigastric distress, abdominal cramping and constipation.

Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida, which may occur during effective therapy.

Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.

Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings.

Central Nervous System: Encephalopathy, aseptic meningitis, convulsive seizures, optic neuropathy, peripheral neuropathy, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness and insomnia.

Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, flushing, nasal congestion, dryness of the mouth (or vagina or vulva) and fever.

Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure and darkened urine.

Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis and fleeting joint pains sometimes resembling “serum sickness.” If patients receiving metronidazole drink alcoholic beverages, they may experience abdominal distress, nausea, vomiting, flushing or headache. A modification of the taste of alcoholic beverages has also been reported. Rare cases of pancreatitis, which abated on withdrawal of the drug, have been reported.

Crohn's disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established. Crohn's disease is not an approved indication for Metronidazole Injection, USP.

Overdosage

Use of dosages of intravenous metronidazole higher than those recommended has been reported. These include the use of 27 mg/kg three times a day for 20 days, and the use of 75 mg/kg as a single loading dose followed by 7.5 mg/kg maintenance doses. No adverse reactions were reported in either of the two cases.

Single oral dose of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported included nausea, vomiting and ataxia.

Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day.

Treatment: There is no specific antidote for overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

Dosage and Administration

In elderly patients the pharmacokinetics of metronidazole may be altered and therefore monitoring of serum levels may be necessary to adjust the metronidazole dosage accordingly.

Treatment of Anaerobic Infections

The recommended dosage schedule for adults is:

Loading Dose	15 mg/kg infused over one hour (approximately 1 g for a 70-kg adult).
Maintenance Dose	7.5 mg/kg infused over one hour every six hours (approximately 500 mg for a 70-kg adult). The first maintenance dose should be instituted six hours following the initiation of the loading dose.

Parenteral therapy may be changed to oral metronidazole when conditions warrant, based upon the severity of the disease and the response of the patient to Metronidazole Injection, USP treatment. The usual adult oral dosage is 7.5 mg/kg every six hours.

A maximum of 4 g should not be exceeded during a 24-hour period.

Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses below those usually recommended should be administered cautiously. Close monitoring of plasma metronidazole levels3 and toxicity is recommended.

In patients receiving Metronidazole Injection, USP in whom gastric secretions are continuously removed by nasogastric aspiration, sufficient metronidazole may be removed in the aspirate to cause a reduction in serum levels.

The dose of Metronidazole Injection, USP should not be specifically reduced in anuric patients since accumulated metabolites may be rapidly removed by dialysis.

The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower respiratory tract and endocardium may require longer treatment.

Prophylaxis:

For surgical prophylactic use, to prevent postoperative infection in contaminated or potentially contaminated colorectal surgery, the recommended dosage schedule for adults is:

1. 15 mg/kg infused over 30 to 60 minutes and completed approximately one hour before surgery; followed by


2. 7.5 mg/kg infused over 30 to 60 minutes at 6 and 12 hours after the initial dose.

It is important that (1) administration of the initial preoperative dose be completed approximately one hour before surgery so that adequate drug levels are present in the serum and tissues at the time of initial incision, and (2) Metronidazole Injection, USP be administered, if necessary, at 6-hour intervals to maintain effective drug levels. Prophylactic use of Metronidazole Injection, USP should be limited to the day of surgery only, following the above guidelines.

Caution: Metronidazole Injection, USP is to be administered by slow intravenous drip infusion only, either as a continuous or intermittent infusion. Additives should not be introduced into Metronidazole Injection, USP. If used with a primary intravenous fluid system, the primary solution should be discontinued during metronidazole infusion. DO NOT USE EQUIPMENT CONTAINING ALUMINUM (e.g., NEEDLES, CANNULAE) THAT WOULD COME IN CONTACT WITH THE DRUG SOLUTION.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

How Supplied

Metronidazole Injection, USP is sterile and is supplied in 100 mL single dose plastic containers, each containing an iso-osmotic, buffered solution of 500 mg metronidazole as follows:

NDC 36000-001-24        500 mg/100 mL

Four groups of 6 bags each are placed in a carton, separated by a divider. Two cartons are then packed into a shipper. Store at 20° - 25°C (68° - 77°F) (see USP controlled room temperature). Protect from light during storage. Avoid excessive heat. Protect from freezing. Do not remove unit from overwrap until ready for use. The overwrap is a moisture barrier. The inner bag maintains the sterility of the product. After removing overwrap, check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard solution, as sterility may be impaired.

Directions for Use of Plastic Container

Metronidazole Injection, USP is a ready-to-use iso-osmotic solution. No dilution or buffering is required. Do not refrigerate. Each container of Metronidazole Injection, USP contains 14 mEq of sodium.

Warning: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.

To open

Tear overwrap at the top and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Check for leaks. Do not add supplementary medication.

Preparation for Administration

1. Suspend container from eyelet support.


2. Remove plastic protector from outlet port at bottom of container.


3. Attach administration set. Refer to complete directions accompanying set.

References

1. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard—Seventh Edition. CLSI document M11-A7. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2007.


2. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Informational Supplement. CLSI document M11-S1 Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA, 2009.


3. Ralph, E.D. and Kirby, W.M.M.: Bioassay of Metronidazole with Either Anaerobic and Aerobic Incubation, J. Infect. Dis. 132:587-591 (Nov.) 1975; or Gulaid, et al.: Determination of Metronidazole and its Major Metabolites in Biological Fluids by High Pressure Liquid Chromatography. BR.J. Clin. Pharmacol. 6:430-432, 1978.

Manufactured for:

Claris Lifesciences Inc.

North Brunswick, NJ 08902

By:

Claris Lifesciences Ltd.,

Ahmedabad, Gujarat, India.

09/2011      1400003464

Metronidazole Injection, USP Container Label

NDC 36000-001-24        100 mL

Metronidazole Injection, USP

500 mg/100 mL

(5 mg/mL)

Sterile Rx Only

Flexible I.V. Plastic container

SINGLE DOSE CONTAINER

Ready-To-Use

Contains Metronidazole 500 mg, Anhydrous Disodiurn Hydrogen Phosphate 47.6 mg, Citric Acid Monohydrate 22.9 mg and Sodium Chloride 790 mg. pH Range 4.5 To 7.0.

Tonicity 310 mOsm/L

Usual Dosage For intravenous infusion only.

See accompanying prescribing information

Cautions Must not be used in series connections.

Additives should not be introduced to this solution.

Manufactured for:

Claris Lifesciences Inc.

North Brunswick, NJ 08902

By: CIaris Lifesciences Ltd.,

India.

Batch No.:

Exp. Date:

09/2011

M.L No. : G/LVP-5

1400003464

METRONIDAZOLE   metronidazole   injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 36000-001 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Metronidazole (Metronidazole ) Metronidazole 500 mg  in 100 mL

Inactive Ingredients Ingredient Name Strength Sodium Chloride 790 mg  in 100 mL Sodium Phosphate, Dibasic Anhydrous 47.6 mg  in 100 mL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 36000-001-24 24 BAG In 1 CARTON contains a BAG 1 100 mL In 1 BAG This package is contained within the CARTON (36000-001-24)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA078084	11/20/2008

Labeler - Claris Lifesciences Inc. (808114537)

Registrant - Claris Lifesciences Limited (862172228)

Establishment
Name	Address	ID/FEI	Operations
Claris Lifesciences Limited		918603338	manufacture, analysis

Revised: 12/2011Claris Lifesciences Inc.

Puregon 300 IU / 0.36 ml, 600 IU / 0.72 ml , 900 IU / 1.08 ml solution for injection

1. Name Of The Medicinal Product

Puregon 300 IU/0.36 ml solution for injection

Puregon 600 IU/0.72 ml solution for injection

Puregon 900 IU/1.08 ml solution for injection

2. Qualitative And Quantitative Composition

One cartridge contains a net total dose of 300 IU recombinant follicle-stimulating hormone (FSH) in 0.36 ml aqueous solution, 600IU recombinant follicle-stimulating hormone (FSH) in 0.72ml aqueous solution or 900IU recombinant follicle-stimulating hormone (FSH) in 1.08ml aqueous solution. The solution for injection contains the active substance follitropin beta, produced by genetic engineering of a Chinese hamster ovary (CHO) cell line, in a concentration of 833 IU/ml aqueous solution. This strength corresponds to 83.3 microgram of protein / ml (specific in vivo bioactivity equal to approximately 10 000 IU FSH / mg protein).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection (injection).

Clear and colourless solution.

In cartridges, designed to be used in conjunction with a pen injector.

4. Clinical Particulars

4.1 Therapeutic Indications

In the female:

Puregon is indicated for the treatment of female infertility in the following clinical situations:

• Anovulation (including polycystic ovarian disease, PCOD) in women who have been unresponsive to treatment with clomifene citrate.

• Controlled ovarian hyperstimulation to induce the development of multiple follicles in medically assisted reproduction programs [e.g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)].

In the male:

• Deficient spermatogenesis due to hypogonadotrophic hypogonadism.

4.2 Posology And Method Of Administration

Treatment with Puregon should be initiated under the supervision of a physician experienced in the treatment of fertility problems.

Posology

Dosage in the female

There are great inter- and intra-individual variations in the response of the ovaries to exogenous gonadotrophins. This makes it impossible to set a uniform dosage scheme. The dosage should, therefore, be adjusted individually depending on the ovarian response. This requires ultrasonography and monitoring of oestradiol levels.

When using the pen-injector, it should be realised that the pen is a precision device which accurately delivers the dose to which it is set. It was shown that on average an 18% higher amount of FSH is given with the pen compared with a conventional syringe. This may be of particular relevance when switching between the pen-injector and a conventional syringe within one treatment cycle. Especially when switching from a syringe to the pen, small dose adjustments may be needed to prevent too high a dose being given.

Based on the results of comparative clinical studies it is considered appropriate to give a lower dosage of Puregonthan generally used for urinary FSH, not only in order to optimise follicular development but also to minimise the risk of unwanted ovarian hyperstimulation.

Clinical experience with Puregon is based on up to three treatment cycles in both indications. Overall experience with IVF indicates that in general the treatment success rate remains stable during the first four attempts and gradually declines thereafter.

•Anovulation

A sequential treatment scheme is recommended starting with daily administration of 50 IU Puregon. The starting dose is maintained for at least seven days. If there is no ovarian response, the daily dose is then gradually increased until follicle growth and/or plasma oestradiol levels indicate an adequate pharmacodynamic response. A daily increase of oestradiol levels of 40-100% is considered to be optimal. The daily dose is then maintained until pre-ovulatory conditions are reached. Pre-ovulatory conditions are reached when there is ultrasonographic evidence of a dominant follicle of at least 18 mm in diameter and/or when plasma oestradiol levels of 300-900 picograms/ml (1000-3000 pmol/l) are attained. Usually, 7 to 14 days of treatment is sufficient to reach this state. The administration of Puregon is then discontinued and ovulation can be induced by administering human chorionic gonadotrophin (hCG).

If the number of responding follicles is too high or oestradiol levels increase too rapidly, i.e. more than a daily doubling for oestradiol for two or three consecutive days, the daily dose should be decreased.

Since follicles of over 14 mm may lead to pregnancies, multiple pre-ovulatory follicles exceeding 14 mm carry the risk of multiple gestations. In that case hCG should be withheld and pregnancy should be avoided to prevent multiple gestations.

•Controlled ovarian hyperstimulation in medically assisted reproduction programs

Various stimulation protocols are applied. A starting dose of 100-225 IU is recommended for at least the first four days. Thereafter, the dose may be adjusted individually, based upon ovarian response. In clinical studies it was shown that maintenance dosages ranging from 75-375 IU for six to twelve days are sufficient, although longer treatment may be necessary.

Puregon can be given either alone, or, to prevent premature luteinisation, in combination with a GnRH agonist or antagonist. When using a GnRH agonist, a higher total treatment dose of Puregon may be required to achieve an adequate follicular response.

Ovarian response is monitored by ultrasonography and measurement of plasma oestradiol levels. When ultrasonographic evaluation indicates the presence of at least three follicles of 16-20 mm, and there is evidence of a good oestradiol response (plasma levels of about 300-400 picograms/ml (1000-1300 pmol/l) for each follicle with a diameter greater than 18 mm), the final phase of maturation of the follicles is induced by administration of hCG. Oocyte retrieval is performed 34-35 hours later.

Dosage in the male

Puregon should be given at a dosage of 450 IU/week, preferably divided in 3 dosages of 150 IU, concomitantly with hCG. The treatment should be continued for at least 3 to 4 months before any improvement in spermatogenesis can be expected. If a patient has not responded after this period, the combination therapy may be continued; current clinical experience indicates that treatment for up to 18 months or longer may be necessary to achieve spermatogenesis.

There is no relevant indication for use of Puregon in children.

Method of administration

Puregon solution for injection in cartridges has been developed for use in the Puregon Pen and should be administered subcutaneously. The injection site should be alternated to prevent lipoatrophy.

Using the pen, injection of Puregon can be carried out by the patient, provided that proper instructions are given by the physician.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients.

• Tumours of the ovary, breast, uterus, testis, pituitary or hypothalamus.

• Undiagnosed vaginal bleeding.

• Primary ovarian failure.

• Ovarian cysts or enlarged ovaries, not related to polycystic ovarian disease (PCOD).

• Malformations of the sexual organs incompatible with pregnancy.

• Fibroid tumours of the uterus incompatible with pregnancy.

• Primary testicular failure.

4.4 Special Warnings And Precautions For Use

• The presence of uncontrolled non-gonadal endocrinopathies (e.g. thyroid, adrenal or pituitary disorders) should be excluded.

• In pregnancies occurring after induction of ovulation with gonadotropic preparations, there is an increased risk of multiple gestations. Appropriate FSH dose adjustment(s) should prevent multiple follicle development. Multiple gestation, especially high order, carries an increased risk of adverse maternal and perinatal outcomes. The patients should be advised of the potential risks of multiple births before starting treatment.

• The first injection of Puregon should be performed under direct medical supervision.

• Since infertile women undergoing assisted reproduction, and particularly IVF, often have tubal abnormalities the incidence of ectopic pregnancies might be increased. Early ultrasound confirmation that a pregnancy is intrauterine is therefore important.

• Rates of pregnancy loss in women undergoing assisted reproduction techniques are higher than in the normal population.

• The incidence of congenital malformations after Assisted Reproductive Technologies (ART) may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g., maternal age, sperm characteristics) and multiple gestations.

• Unwanted ovarian hyperstimulation: in the treatment of female patients, ultrasonographic assessment of follicular development, and determination of oestradiol levels should be performed prior to treatment and at regular intervals during treatment. Apart from the development of a high number of follicles, oestradiol levels may rise very rapidly, e.g. more than a daily doubling for two or three consecutive days, and possibly reaching excessively high values. The diagnosis of ovarian hyperstimulation may be confirmed by ultrasound examination. If this unwanted ovarian hyperstimulation occurs (i.e. not as part of controlled ovarian hyperstimulation in medically assisted reproduction programs), the administration of Puregon should be discontinued. In that case pregnancy should be avoided and hCG must be withheld, because it may induce, in addition to multiple ovulation, the ovarian hyperstimulation syndrome (OHSS). Clinical symptoms and signs of mild ovarian hyperstimulation syndrome are abdominal pain, nausea, diarrhoea, and mild to moderate enlargement of ovaries and ovarian cysts. Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in associated with ovarian hyperstimulation syndrome. In rare cases severe ovarian hyperstimulation syndrome occurs, which may be life-threatening. This is characterised by large ovarian cysts (prone to rupture), ascites, often hydrothorax and weight gain. In rare instances, venous or arterial thromboembolism may occur in association with OHSS.

• There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. It is not yet established whether or not treatment with gonadotrophins increases the baseline risk of these tumours in infertile women.

• Women with generally recognised risk factors for thrombosis, such as a personal or family history, severe obesity (Body Mass Index > 30 kg/m2) or thrombophilia, may have an increased risk of venous or arterial thrombo-embolic events, during or following treatment with gonadotrophins. In these women the benefits of IVF treatment need to be weighed against the risks. It should be noted, however, that pregnancy itself also carries an increased risk of thrombosis.

• Puregon may contain traces of streptomycin and/or neomycin. These antibiotics may cause hypersensitivity reactions in susceptible persons.

• Elevated endogeneous FSH levels in men are indicative of primary testicular failure. Such patients are unresponsive to Puregon/hCG therapy.

• In men, semen analysis is recommended 4 to 6 months after the beginning of treatment in assessing the response.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of Puregon and clomifene citrate may enhance the follicular response. After pituitary desensitisation induced by a GnRH agonist, a higher dose of Puregon may be necessary to achieve an adequate follicular response.

4.6 Pregnancy And Lactation

There is no indication for use of Puregon during pregnancy. No teratogenic risk has been reported, following controlled ovarian hyperstimulation, in clinical use with gonadotropins. In case of exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of recombinant FSH. However, to date, no particular malformative effect has been reported. No teratogenic effect has been observed in animal studies.

Puregon should not be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Puregon has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Clinical use of Puregon by the intramuscular or subcutaneous routes may lead to local reactions at the site of injection: bruising, pain, redness, swelling and itching are commonly reported (3% of all patients treated). The majority of these local reactions are mild and transient in nature. Generalised hypersensitivity reactions including erythema, urticaria, rash and pruritus have been observed uncommonly (approximately 0.1% of all patients treated with Puregon).

Treatment of women:

In approximately 4% of the women treated with Puregon in clinical trials, signs and symptoms related to ovarian hyperstimulation syndrome (OHSS) have been reported (see section 4.4).

Other undesirable effects related to this syndrome were observed in clinical studies. These include pelvic pain and/or congestion, abdominal pain and/or distension, breast complaints (breast tenderness, pain and/or engorgement), ovarian enlargement, and spontaneous abortion. They were all reported at an incidence of approximately 1% (pelvic pain and abdominal distension) or less.

A slightly increased risk of ectopic pregnancy and multiple gestations has been seen.

Other more general symptoms that have been reported include headache and nausea (in up to 1% of the women treated with Puregon)

In rare instances, thromboembolism has been associated with Puregon/hCG therapy as with other gonadotrophins.

Treatment of men:

Gynaecomastia and acne may occur occasionally during Puregon/hCG therapy. These are known effects of hCG treatment.

4.9 Overdose

No data on acute toxicity of Puregon in humans is available, but the acute toxicity of Puregon and of urinary gonadotrophin preparations in animal studies has been shown to be very low. Too high a dosage of FSH may lead to hyperstimulation of the ovaries (see section 4.4).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: gonadotrophins; ATC code: G03G A06.

Puregon contains a recombinant FSH. This is produced by recombinant DNA technology, using a Chinese hamster ovary cell line transfected with the human FSH subunit genes. The primary amino acid sequence is identical to that of natural human FSH. Small differences in the carbohydrate chain structure are known to exist.

FSH is indispensable in normal follicular growth and maturation, and gonadal steroid production. In the female the level of FSH is critical for the onset and duration of follicular development, and consequently for the timing and number of follicles reaching maturity. Puregon can thus be used to stimulate follicular development and steroid production in selected cases of disturbed gonadal function. Furthermore Puregon can be used to promote multiple follicular development in medically assisted reproduction programs [e.g. in vitro fertilisation/embryo transfer (IVF/ET), gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)]. Treatment with Puregon is generally followed by administration of hCG to induce the final phase of follicle maturation, resumption of meiosis and rupture of the follicle.

In men deficient in FSH, Puregon should be used concomitantly with hCG for at least four months to promote spermatogenesis.

5.2 Pharmacokinetic Properties

After subcutaneous administration of Puregon, maximum concentration of FSH is reached within about 12 hours. Due to the sustained release from the injection site and the elimination half-life of about 40 hours (ranging from 12 to 70 hours), FSH levels remain increased for 24-48 hours. Due to the relatively long elimination half-life, repeated administration of the same dose will lead to plasma concentrations of FSH that are approximately 1.5-2.5 times higher than after single dose administration. This increase enables therapeutic FSH concentrations to be reached.

The absolute bioavailability of subcutaneously administered Puregon is approximately 77%. Recombinant FSH is biochemically very similar to urinary human FSH and is distributed, metabolised, and excreted in the same way.

5.3 Preclinical Safety Data

Single-dose administration of Puregon to rats induced no toxicologically significant effects. In repeated-dose studies in rats (two weeks) and dogs (13 weeks) up to 100-fold the maximal human dose, Puregon induced no toxicologically significant effects. Puregon showed no mutagenic potential in the Ames test and in the in vitro chromosome aberration test with human lymphocytes.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Puregon 300 IU/0.36 ml, Puregon 600IU/0.72ml and Puregon 900IU/1.08ml solution for injection contains:

sucrose

sodium citrate

L

polysorbate 20

benzyl alcohol

water for injections.

The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

3 years.

Once the rubber inlay of a cartridge is pierced by a needle, the product may be stored for a maximum of 28 days.

6.4 Special Precautions For Storage

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

Keep the cartridge in the outer carton.

For patient convenience, Puregon may be stored at or below 25 ºC by the patient for a single period of not more than 3 months.

6.5 Nature And Contents Of Container

Puregon 300IU/0.36 ml of solution in 1.5 ml cartridge (type I glass) with a grey rubber piston and an aluminium crimp-cap with a rubber inlay.

Pack of 1 cartridge and 6 needles to be used with the Puregon Pen.

Cartridges contain a minimum of 400 IU FSH activity in 0.480 ml aqueous solution, which is sufficient for a net total dose of 300 IU.

Puregon 600IU/0.72 ml of solution in 1.5ml cartridge (type I glass) with a grey rubber piston and an aluminium crimp-cap with a rubber inlay.

Pack of 1 cartridge and 6 needles to be used with the Puregon Pen.

Cartridges contain a minimum of 700 IU FSH activity in 0.840 ml aqueous solution, which is sufficient for a net total dose of 600 IU.

Puregon 900IU/1.08 ml of solution in 1.5ml cartridge (type I glass) with a grey rubber piston and an aluminium crimp-cap with a rubber inlay.

Pack of 1 cartridge and 9 needles to be used with the Puregon Pen.

Cartridges contain a minimum of 1025 IU FSH activity in 1.230 ml aqueous solution, which is sufficient for a net total dose of 900 IU.

6.6 Special Precautions For Disposal And Other Handling

Do not use if the solution contains particles or if the solution is not clear.

Puregon 300 IU/0.36 ml, 600 IU/0.72 ml and 900 IU/1.08ml solution for injection is designed for use in conjunction with the Puregon Pen. The instructions for using the pen must be followed carefully.

Air bubbles must be removed from the cartridge before injection (see instructions for using the pen).

Empty cartridges must not be refilled.

Puregon cartridges are not designed to allow any other drug to be mixed in the cartridges.

Discard used needles immediately after injection.

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

7. Marketing Authorisation Holder

N.V. Organon

Kloosterstraat 6

Postbus 20

5340 BH Oss

The Netherlands

8. Marketing Authorisation Number(S)

EU/1/96/008/038 (Puregon 300 IU/0.36 ml solution for injection)

EU/1/96/008/039 (Puregon 600 IU/0.72 ml solution for injection)

EU/1/96/008/041 (Puregon 900 IU/1.08ml solution for injection)

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 3 May 1996

Date of last renewal: 29 May 2006

10. Date Of Revision Of The Text

23 November 2009

11. LEGAL CATEGORY

Prescription Only Medicine

Puregon PEN/12-09/2

RA 2535UK - S8 (ref. 31)

Vectibix

Vectibix 20 mg/ml concentrate for solution for infusion

panitumumab

Read all of this leaflet carefully before you start using this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


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

In this leaflet:

• 1. What Vectibix is and what it is used for


• 2. Before you use Vectibix


• 3. How to use Vectibix


• 4. Possible side effects


• 5. How to store Vectibix


• 6. Further information

What Vectibix Is And What It Is Used For

Vectibix is used in the treatment of metastatic colorectal carcinoma (cancer of the bowel) after failure of chemotherapy (medicines used to treat cancer) treatment.

Vectibix is for use in adults 18 years and over.

Vectibix contains the active substance panitumumab, which belongs to a group of medicines called monoclonal antibodies. Monoclonal antibodies are proteins, which specifically recognise and attach (bind) to other unique proteins in the body.

Panitumumab recognises and binds specifically to a protein known as epidermal growth factor receptor (EGFR), which is found on the surface of some cancer cells. When growth factors (other body proteins) attach to the EGFR, the cancer cell is stimulated to grow and divide. Panitumumab binds onto the EGFR and prevents the cancer cell from receiving the messages it needs for growth and division.

Before You Use Vectibix

Do not use Vectibix

• If you have ever had a severe or life threatening allergic (hypersensitivity) reaction to panitumumab or any of the other ingredients of Vectibix.


• if you have previously had or have evidence of interstitial pneumonitis (swelling of the lungs causing coughing and difficulty breathing) or pulmonary fibrosis (scarring and thickening in the lungs with shortness of breath).

Take special care with Vectibix

Your doctor will check your blood levels of several substances such as magnesium, and other electrolyte levels such as calcium and potassium in your blood before you start Vectibix treatment. If these levels are too low, your doctor may prescribe you appropriate supplements.

During treatment with Vectibix

You may experience dermatologic toxicities (skin reactions), if these worsen or become intolerable please tell your doctor or nurse immediately.

It is recommended that you limit sun exposure whilst receiving Vectibix and if you are experiencing skin reactions as sunlight can worsen these. Wear sunscreen and a hat if you are going to be exposed to sunlight.

Your doctor will ask you to come in for tests to monitor hypomagnesaemia (low magnesium levels in the blood) and hypocalcaemia (low calcium levels in the blood) periodically during your treatment, and for up to 8 weeks after you have finished your treatment.

Using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Vectibix has not been tested in pregnant women. It is important to tell your doctor if you are pregnant; think you may be pregnant; or plan to get pregnant. Vectibix could affect your ability to stay pregnant.

If you are a woman of child bearing potential, you should use suitable methods of contraception during treatment with Vectibix and for 6 months after the last dose.

Do not breast-feed your baby during treatment with Vectibix and for 3 months after the last dose.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

No studies on the effects on the ability to drive and use machines have been performed. You should speak with your doctor before driving or using machines, as some side effects may impair your ability to do so safely.

How To Use Vectibix

Vectibix will be administered in a healthcare facility under the supervision of a doctor experienced in the use of anti-cancer medicines.

Vectibix is administered intravenously (into a vein) with an infusion pump (a device that gives a slow injection).

The recommended dose of Vectibix is 6 mg/kg (milligrams per kilogram of body weight) given once every two weeks. The treatment will usually be given over a period of approximately 60 minutes.

Vectibix Side Effects

Like all medicines, Vectibix can cause side effects, although not everybody gets them.

Very common side effects (seen in more than 1 in 10 people who take Vectibix) were:

• Acne-like rash; acne; pruritus (itching); erythema (redness of skin); rash; skin exfoliation (flaking skin); dry skin; skin fissures (cracks in the skin); exfoliating rash (flaking rash)


• diarrhoea; nausea; vomiting; abdominal pain; constipation;


• stomatitis (chapped lips, mouth ulcers and cold sores);


• fatigue (extreme tiredness);


• pyrexia (fever or high temperature);


• paronychia (nail infection);


• cough; dyspnoea (breathing difficulties).

Common side effects (seen in more than 1, but less than 10 in 100 people taking Vectibix) were:

• infusion type reactions which may include signs and symptoms such as abdominal pain, back pain, breathing difficulties, chest pain, flushing, rapid heart rate; hypotension (low blood pressure); hypertension (high blood pressure); vomiting; chills; new onset of facial swelling and/or swelling of the mouth; and/or pyrexia (fever or high temperature));


• hand-foot syndrome (redness and swelling of palms of hands or soles of feet);


• onycholysis (loosening of the nails); nail disorder;


• rash pustular (skin rash with pus-filled blisters);


• eye infection; eyelid infection;


• cellulitis (spreading infection below the skin);


• hypomagnesaemia (low magnesium levels in the blood);


• hypocalcaemia (low calcium levels in the blood);


• hypokalaemia (low potassium levels in the blood);


• dehydration;


• nasal dryness; epistaxis (nose bleed);


• headache; dizziness;


• rash papular (bumpy rash); rash pruritic (itchy rash); rash erythematous (red skin rash); rash macular (spotty rash); rash maculo-papular (rash with bumps and spots); skin ulcer; scab;


• conjunctivitis (eye inflammation); growth of eyelashes and lacrimation increased (flow of tears); ocular hyperaemia (redness of the eye); dry eye; eye pruritus (itchy eyes); eyelid irritation; eye irritation;


• pulmonary embolism (blood clot in the lung);


• mucosal inflammation (inflammation of the mouth); dry mouth;


• onycholysis (breaking of the nails);


• hypertrichosis (excess hair growth); alopecia (hair loss);

Uncommon side effects (seen in less than 1 in 100, but more than 1 in 1000 people taking Vectibix) were:

• bronchospasm (constriction of the airways);


• anaphylactic reactions (severe allergic reaction);


• flushing; hypotension (low blood pressure); hypertension (high blood pressure);


• cyanosis (blue coloration of the skin and mucous membranes).

Rare side effects (seen in less than 1 in 1000, but more than 1 in 10,000 people taking Vectibix) were:

• angioedema (swelling of the mouth, face and throat causing difficulty in breathing).

Infusion-type reactions, which may include signs and symptoms such as chills, new onset of facial swelling, breathing difficulties, vomiting and/or fever or pyrexia (high temperature) may appear several hours or days after an infusion. If any of these side effects gets serious, please tell your doctor.

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

Important information about some of the ingredients of Vectibix

This medicinal product contains 0.150 mmol sodium (which is 3.45 mg sodium) per ml of concentrate. To be taken into consideration by patients on a controlled sodium diet.

How To Store Vectibix

Vectibix will be stored in the healthcare facility where it is used.

Keep out of the reach and sight of children.

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Store in the original carton in order to protect from light.

Do not use Vectibix after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Vectibix contains

The active substance is panitumumab 20 mg/ml.

The other ingredients of Vectibix are sodium chloride, sodium acetate trihydrate, acetic acid (glacial) and water for injections.

What Vectibix looks like and contents of the pack

Vectibix is a colourless liquid that may contain visible particles and is supplied in a vial. Each pack contains one vial of either 5 ml, 10 ml or 20 ml of concentrate.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

The Netherlands

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

United Kingdom

Amgen Limited

Tel:+44 (0)1223 420305

This leaflet was last approved in April 2010.

Detailed information on this medicine is available on the European Medicines Agency web site: http://www.emea.europa.eu/

This medicine has been given “conditional approval”.

This means that there is more evidence to come about this medicine.

The European Medicines Agency (EMA) will review new information on the medicine every year and this leaflet will be updated as necessary.

Amlodipine

Dosage Form: tablet
FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

Hypertension

Amlodipine besylate tablets, USP are indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

Coronary Artery Disease (CAD)

Chronic Stable Angina

Amlodipine besylate tablets, USP are indicated for the symptomatic treatment of chronic stable angina. Amlodipine besylate tablets, USP may be used alone or in combination with other antianginal agents.

Vasospastic Angina (Prinzmetal’s or Variant Angina)

Amlodipine besylate tablets, USP are indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine besylate tablets, USP may be used as monotherapy or in combination with other antianginal agents.

Angiographically Documented CAD

In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, Amlodipine besylate tablets, USP are indicated to reduce the risk of hospitalization due to angina and to reduce the risk of a coronary revascularization procedure.

2. DOSAGE AND ADMINISTRATION

Adults

The usual initial antihypertensive oral dose of Amlodipine is 5 mg once daily with a maximum dose of 10 mg once daily.  

Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding Amlodipine to other antihypertensive therapy.

Adjust dosage according to each patient’s need. In general, titration should proceed over 7 to 14 days so that the physician can fully assess the patient’s response to each dose level. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.

The recommended dose for chronic stable or vasospastic angina is 5 to 10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect [see Adverse Reactions (6)].

The recommended dose range for patients with coronary artery disease is 5 to 10 mg once daily. In clinical studies, the majority of patients required 10 mg [see Clinical Studies (14.4)].

Children

The effective antihypertensive oral dose in pediatric patients ages 6–17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology (12.4), Clinical Studies (14.1)].

3. DOSAGE FORMS AND STRENGTHS

2.5, 5, and 10 mg Tablets

4. CONTRAINDICATIONS

Amlodipine is contraindicated in patients with known sensitivity to Amlodipine.

5. WARNINGS AND PRECAUTIONS

Hypotension

Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.  

Increased Angina or Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of Amlodipine, particularly in patients with severe obstructive coronary artery disease.

Beta-Blocker Withdrawal

Amlodipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.

Patients with Hepatic Failure

Because Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with impaired hepatic function, titrate slowly when administering Amlodipine to patients with severe hepatic impairment.

6. ADVERSE REACTIONS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with Amlodipine was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with Amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing Amlodipine (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of Amlodipine due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence (%) of side effects that occurred in a dose related manner are as follows:

Adverse Event	2.5 mg  N=275	5 mg  N=296	10 mg  N=268	Placebo  N=520
Edema	1.8	3.0	10.8	0.6
Dizziness	1.1	3.4	3.4	1.5
Flushing	0.7	1.4	2.6	0.0
Palpitation	0.7	1.4	4.5	0.6

Other adverse experiences that were not clearly dose related but were reported with an incidence greater than 1% in placebo-controlled clinical trials include the following:

Placebo-Controlled Studies

	Amlodipine (%) (N=1730)	Placebo (%) (N=1250)
Headache	7.3	7.8
Fatigue	4.5	2.8
Nausea	2.9	1.9
Abdominal Pain	1.6	0.3
Somnolence	1.4	0.6

For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with Amlodipine treatment as shown in the following table:

	Amlodipine		Placebo
Adverse Event	Male=%  (N=1218)	Female=%  (N=512)	Male=%  (N=914)	Female=%  (N=336)
Edema	5.6	14.6	1.4	5.1
Flushing	1.5	4.5	0.3	0.9
Palpitations	1.4	3.3	0.9	0.9
Somnolence	1.3	1.6	0.8	0.3

The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.

Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.

Gastrointestinal: anorexia, constipation, dyspepsia,1 dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

General: allergic reaction, asthenia,1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal System: arthralgia, arthrosis, muscle cramps,1 myalgia.

Psychiatric: sexual dysfunction (male1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

Respiratory System: dyspnea,1 epistaxis.

Skin and Appendages: angioedema, erythema multiforme, pruritus,1 rash,1 rash erythematous, rash maculopapular.

Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.

Urinary System: micturition frequency, micturition disorder, nocturia.

Autonomic Nervous System: dry mouth, sweating increased.

Metabolic and Nutritional: hyperglycemia, thirst.

Hemopoietic: leukopenia, purpura, thrombocytopenia.

1 These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

The following events occurred in <0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.

Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.

Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.

In the CAMELOT and PREVENT studies [see Clinical Studies (14.4)], the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.

Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of Amlodipine.

Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

7. DRUG INTERACTIONS

In Vitro Data

In vitro data indicate that Amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Cimetidine

Co-administration of Amlodipine with cimetidine did not alter the pharmacokinetics of Amlodipine.

Grapefruit Juice

Co-administration of 240 mL of grapefruit juice with a single oral dose of Amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of Amlodipine.

Magnesium and Aluminum Hydroxide Antacid

Co-administration of a magnesium and aluminum hydroxide antacid with a single dose of Amlodipine had no significant effect on the pharmacokinetics of Amlodipine.

Sildenafil

A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of Amlodipine. When Amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin

Co-administration of multiple 10 mg doses of Amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Simvastatin

Co-administration of multiple doses of 10 mg of Amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on Amlodipine to 20 mg daily.

Digoxin

Co-administration of Amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Ethanol (Alcohol)

Single and multiple 10 mg doses of Amlodipine had no significant effect on the pharmacokinetics of ethanol.

Warfarin

Co-administration of Amlodipine with warfarin did not change the warfarin prothrombin response time.

CYP3A4 Inhibitors

Co-administration of a 180 mg daily dose of diltiazem with 5 mg Amlodipine in elderly hypertensive patients resulted in a 60% increase in Amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change Amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of Amlodipine to a greater extent. Monitor for symptoms of hypotension and edema when Amlodipine is co-administered with CYP3A4 inhibitors.

CYP3A4 Inducers

No information is available on the quantitative effects of CYP3A4 inducers on Amlodipine. Blood pressure should be closely monitored when Amlodipine is co-administered with CYP3A4 inducers.

Drug/Laboratory Test Interactions

None known.

8. USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with Amlodipine maleate at doses up to 10 mg Amlodipine/kg/day (respectively, 8 times2 and 23 times2 the maximum recommended human dose of 10 mg on a mg/m2 basis) during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving Amlodipine maleate at a dose equivalent to 10 mg Amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.  

2 Based on patient weight of 50 kg.

Nursing Mothers

It is not known whether Amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered.

Pediatric Use

Effect of Amlodipine on blood pressure in patients less than 6 years of age is not known.

Geriatric Use

Clinical studies of Amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of Amlodipine with a resulting increase of AUC of approximately 40–60%, and a lower initial dose may be required [see Dosage and Administration (2.1)].

10. OVERDOSAGE

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of Amlodipine is limited.

Single oral doses of Amlodipine maleate equivalent to 40 mg Amlodipine/kg and 100 mg Amlodipine/kg in mice and rats, respectively, caused deaths. Single oral Amlodipine maleate doses equivalent to 4 or more mg Amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.

If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As Amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

11. DESCRIPTION

Amlodipine besylate is the besylate salt of Amlodipine, a long-acting calcium channel blocker.

Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±) - 2 - [(2 - aminoethoxy)methyl] - 4 - (2 - chlorophenyl) - 1,4 - dihydro - 6 - methyl - 3,5 - pyridinedicarboxylate, monobenzenesulphonate. Its molecular formula is C20H25CIN2O5•C6H6O3S, and its structural formula is:

Amlodipine besylate, USP is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate tablets, USP are formulated as white tablets equivalent to 2.5, 5, and 10 mg of Amlodipine for oral administration. In addition to the active ingredient, Amlodipine besylate, USP each tablet contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.

12. CLINICAL PHARMACOLOGY

Mechanism of Action

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by Amlodipine. Within the physiologic pH range, Amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The precise mechanisms by which Amlodipine relieves angina have not been fully delineated, but are thought to include the following:

Exertional Angina: In patients with exertional angina, Amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of Amlodipine in vasospastic (Prinzmetal’s or variant) angina.

Pharmacodynamics

Hemodynamics: Following administration of therapeutic doses to patients with hypertension, Amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of Amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of Amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with Amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90–104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of Amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with Amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, Amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Electrophysiologic Effects: Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving Amlodipine and concomitant beta-blockers. In clinical studies in which Amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, Amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Pharmacokinetics and Metabolism

After oral administration of therapeutic doses of Amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of Amlodipine is not altered by the presence of food.

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of Amlodipine are reached after 7 to 8 days of consecutive daily dosing.

The pharmacokinetics of Amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

Elderly patients and patients with hepatic insufficiency have decreased clearance of Amlodipine with a resulting increase in AUC of approximately 40–60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.

Pediatric Patients

Sixty-two hypertensive patients aged 6 to 17 years received doses of Amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.

13. NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Rats and mice treated with Amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 Amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m2 basis, similar to the maximum recommended human dose of 10 mg Amlodipine/day.3 For the rat, the highest dose was, on a mg/m2 basis, about twice the maximum recommended human dose.3

Mutagenicity studies conducted with Amlodipine maleate revealed no drug related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with Amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg Amlodipine/kg/day (8 times the maximum recommended human dose3 of 10 mg/day on a mg/m2 basis).

3 Based on patient weight of 50 kg

14. CLINICAL STUDIES

Effects in Hypertension

Adult Patients

The antihypertensive efficacy of Amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on Amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients and in white patients.

Pediatric Patients

Two hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized first to Amlodipine 2.5 or 5 mg once daily for 4 weeks and then randomized again to the same dose or to placebo for another 4 weeks. Patients receiving 2.5 mg or 5 mg at the end of 8 weeks had significantly lower systolic blood pressure than those secondarily randomized to placebo. The magnitude of the treatment effect is difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg dose and 3.3 mmHg systolic on the 2.5 mg dose. Adverse events were similar to those seen in adults.

Effects in Chronic Stable Angina

The effectiveness of 5 to 10 mg/day of Amlodipine in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (684 Amlodipine, 354 placebo) with chronic stable angina. In 5 of the 8 studies, significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for Amlodipine 10 mg, and averaged 7.9% (38 sec) for Amlodipine 5 mg. Amlodipine 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of Amlodipine in angina patients has been demonstrated over long-term dosing. In patients with angina, there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).

Effects in Vasospastic Angina

In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, Amlodipine therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p<0.01). Two of 23 Amlodipine and 7 of 27 placebo patients discontinued from the study due to lack of clinical improvement.

Effects in Documented Coronary Artery Disease

In PREVENT, 825 patients with angiographically documented coronary artery disease were randomized to Amlodipine (5 to 10 mg once daily) or placebo and followed for 3 years. Although the study did not show significance on the primary objective of change in coronary luminal diameter as assessed by quantitative coronary angiography, the data suggested a favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD.

CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction <40%. Patients (76% males, 89% Caucasian, 93% enrolled at US sites, 89% with a history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with a stent) were randomized to double-blind treatment with either Amlodipine (5 to 10 mg once daily) or placebo in addition to standard care that included aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%), anti-coagulants (40%), and diuretics (32%), but excluded other calcium channel blockers. The mean duration of follow-up was 19 months. The primary endpoint was the time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease. A total of 110 (16.6%) and 151 (23.1%) first events occurred in the Amlodipine and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI: 0.540–0.884, p = 0.003). The primary endpoint is summarized in Figure 1 below. The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures (see Table 1). Effects in various subgroups are shown in Figure 2.

In an angiographic substudy (n=274) conducted within CAMELOT, there was no significant difference between Amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular ultrasound.

Figure 1 - Kaplan-Meier Analysis of Composite Clinical Outcomes for Amlodipine versus Placebo  

Figure 2 – Effects on Primary Endpoint of Amlodipine versus Placebo across Sub-Groups

Table 1 below summarizes the significant composite endpoint and clinical outcomes from the composites of the primary endpoint. The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, myocardial infarction, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate a significant difference between Amlodipine and placebo.  

Table 1.  Incidence of Significant Clinical Outcomes for CAMELOT

* Total patients with these events
Clinical Outcomes  N (%)	Amlodipine (N=663)	Placebo (N=655)	Risk Reduction (p-value)
Composite CV	110	151	31%
Endpoint	(16.6)	(23.1)	(0.003)
Hospitalization for	51	84	42%
Angina*	(7.7)	(12.8)	(0.002)
Coronary	78	103	27%
Revascularization*	(11.8)	(15.7)	(0.033)

Studies in Patients with Heart Failure

Amlodipine has been compared to placebo in four 8–12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction. In a long-term (follow-up at least 6 months, mean 13.8 months) placebo-controlled mortality/morbidity study of Amlodipine 5 to 10 mg in 1153 patients with NYHA Classes III (n=931) or IV (n=222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, Amlodipine had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on Amlodipine and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study.

Another study (PRAISE-2) randomized patients with NYHA Class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n=827) or Amlodipine (n=827) and followed them for a mean of 33 months. There was no statistically significant difference between Amlodipine and placebo in the primary endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29% increase on Amlodipine). With Amlodipine there were more reports of pulmonary edema.

16. HOW SUPPLIED/STORAGE AND HANDLING

2.5 mg Tablets

Amlodipine besylate-2.5 mg tablets, USP (Amlodipine besylate, USP, equivalent to 2.5 mg of Amlodipine per tablet) are supplied as white, circular, flat-faced, beveled-edged tablets engraved with ‘1022’ on one side and ‘2.5mg’ on the other side and supplied as follows:

NDC 13668-022-30                       Bottle of 30

NDC 13668 - 022 - 90                      Bottle of 90

NDC 13668 - 022 - 01                      Bottle of 100

NDC 13668-022-03                       Bottle of 300

NDC 13668 - 022 - 05                      Bottle of 500

NDC 13668 - 022 - 10                      Bottle of 1000

NDC 13668 - 022 - 74                      Unit Dose Cartons of 100 (10 x 10)

5 mg Tablets

Amlodipine besylate-5 mg tablets, USP (Amlodipine besylate, USP, equivalent to 5 mg of Amlodipine per tablet) are white, circular, flat-faced, beveled-edged tablets engraved with ‘1023’ on one side and ‘5mg’ on the other side and supplied as follows:

NDC 13668-023-30                       Bottle of 30

NDC 13668 - 023 - 90                      Bottle of 90

NDC 13668-023-01                       Bottle of 100

NDC 13668-023-03                       Bottle of 300

NDC 13668-023-05                       Bottle of 500

NDC 13668 - 023 - 10                      Bottle of 1000

NDC 13668 - 023 - 48                      Bottle of 4100

NDC 13668 - 023 - 74                      Unit Dose Cartons of 100 (10 x 10)

10 mg Tablets

Amlodipine besylate-10 mg tablets, USP (Amlodipine besylate, USP, equivalent to 10 mg of Amlodipine per tablet) are white, circular, flat-faced, beveled-edged tablets engraved with ‘1024’ on one side and ‘10mg’ on the other side and supplied as follows:

NDC 13668-024-30                       Bottle of 30

NDC 13668-024-90                       Bottle of 90

NDC 13668-024-01                       Bottle of 100

NDC 13668-024-03                       Bottle of 300

NDC 13668 - 024 - 05                      Bottle of 500

NDC 13668 - 024 - 10                      Bottle of 1000

NDC 13668 - 024 - 20                      Bottle of 2000

NDC 13668 - 024 - 74                      Unit Dose Cartons of 100 (10 x 10)           

Storage

Store at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F). [See USP Controlled Room Temperature.]

Manufactured by:

TORRENT PHARMACEUTICALS LTD., Indrad-382 721,

Dist. Mehsana, INDIA.

For:

TORRENT PHARMA INC., 5380 Holiday Terrace,

Suite 40, Kalamazoo, Michigan 49009.

8029473                                                                                                                                                         Revised January 2012

PATIENT INFORMATION

Amlodipine Besylate Tablets, USP

Rx Only

Read this information carefully before you start taking Amlodipine besylate tablets and each time you refill your prescription. There may be new information. This information does not replace talking with your doctor. If you have any questions about Amlodipine besylate tablets, ask your doctor. Your doctor will know if Amlodipine besylate tablets are right for you.

What are Amlodipine besylate tablets?

Amlodipine besylate tablets are a type of medicine known as a calcium channel blocker (CCB). It is used to treat high blood pressure (hypertension) and a type of chest pain called angina. It can be used by itself or with other medicines to treat these conditions.

High Blood Pressure (hypertension)

High blood pressure comes from blood pushing too hard against your blood vessels. Amlodipine besylate tablets relax your blood vessels, which lets your blood flow more easily and helps lower your blood pressure. Drugs that lower blood pressure lower your risk of having a stroke or heart attack.

Angina

Angina is a pain or discomfort that keeps coming back when part of your heart does not get enough blood. Angina feels like a pressing or squeezing pain, usually in your chest under the breastbone. Sometimes you can feel it in your shoulders, arms, neck, jaws, or back. Amlodipine besylate tablets can relieve this pain.  

Who should not use Amlodipine besylate tablets?

Do not use Amlodipine besylate tablets if you are allergic to Amlodipine (the active ingredient in Amlodipine besylate tablets), or to the inactive ingredients. Your doctor or pharmacist can give you a list of these ingredients.   

What should I tell my doctor before taking Amlodipine besylate tablets?

Tell your doctor about any prescription and non-prescription medicines you are taking, including natural or herbal remedies. Tell your doctor if you:

• ever had heart disease


• ever had liver problems


• are pregnant, or plan to become pregnant. Your doctor will decide if Amlodipine besylate tablets are the best treatment for you.


• are breast-feeding. Do not breast-feed while taking Amlodipine besylate tablets. You can stop breast-feeding or take a different medicine.

How should I take Amlodipine besylate tablets?

• Take Amlodipine besylate tablets once a day, with or without food.


• It may be easier to take your dose if you do it at the same time every day, such as with breakfast or dinner, or at bedtime. Do not take more than one dose of Amlodipine besylate tablets at a time.  


• If you miss a dose, take it as soon as you remember. Do not take Amlodipine besylate tablets if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time.


• Other medicines: You can use nitroglycerin and Amlodipine besylate tablets together. If you take nitroglycerin for angina, don’t stop taking it while you are taking Amlodipine besylate tablets.


• While you are taking Amlodipine besylate tablets, do not stop taking your other prescription medicines, including any other blood pressure medicines, without talking to your doctor.


• If you took too much Amlodipine besylate tablets, call your doctor or Pois