CONSliLTANTS TO THE PHARMACEUTICAL AND … 2011/2011P-0459.01.pdfMay 27, 2011 · CONSliLTANTS TO THE PHARMACEUTICAL AND ALLIED INDUSTRIES . ... Pentazocine Hydrochloride and ... PENTAZOCINE

LACHMAN CONSULTANT SERVICES INC CONSliLTANTS TO THE PHARMACEUTICAL AND ALLIED INDUSTRIES

1600 STEWART AVENUE WESTBURY NY 11590 (516) 222-6222 bull FAX (516) 683-1887

1m I JUN - 8 P 2 2 0

June 72011

OVERNIGHT COURIER 672011

Division of Dockets Management Food and Drug Administration (HFA-305) Department of Health and Human Services 5630 Fishers Lane Room 1061 Rockville MD 20852

CITIZEN PETITION

Dear Sir or Madam

The undersigned submits this petition in quadruplicate pursuant to Section 505(j)(2)(C) of the Federal Food Drug and Cosmetic Act and in accordance with 21 CFR 1030 on behalf of a client requesting the Commissioner of the Food and Drug Administration to declare that the drug products Pentazocine Hydrochloride and Acetaminophen Tablets 125 mg325 mg and 25 mg325 mg are suitable for consideration in an abbreviated new drug application (ANDA)

A Action Requested

The petitioner requests that the Commissioner of the Food and Drug Administration declare that Pentazocine Hydrochloride and Acetaminophen Tablets 125 mg325 mg and 25 mg325 mg are suitable for submission as an ANDA The reference-listed drug product (RLD) upon which this petition is based is Pentazocine Hydrochloride and Acetaminophen Tablets 25 mg650 mg ANDA 74-699 held by Watson Pharma Inc as designated in the Orange Book (see copy of the page from the current Electronic Edition of the Approved Drug Products with Therapeutic Eguivalence Evaluations (ie Orange Book Attachment 1raquo Supportive reference is also made to NDA 16-891 for Talwinreg Compound (pentazocine hydrochloride and aspirin) Tablets 125 mg325 mg held by Sanofi Aventis to demonstrate that the Agency finds no questions of safety or efficacy with the strengths proposed in this petition We note that although NDA 16-891 currently is listed in the discontinued section of the Orange Book (Attachment 2) a Citizen Petition has been filed requesting that the Commissioner of the Food and Drug Administration determine whether Talwinreg Compound (aspirin and pentazocine hydrochloride) Tablets 325 mg125 mg (NDA 16-891) by Sanofi Aventis has been voluntarily withdrawn or withheld from sale for safety or efficacy reasons Thus the petitioner is seeking a change in dosage strength of the ingredients (from 25 mg650 mg to 125 mg325 mg and 25 mg325 mg) from that of the listed drug product

B Statement of Grounds

The Federal Food Drug and Cosmetic Act provides for the submission of an Abbreviated New Drug Application for a drug product that differs in dosage strength from that of the listed drug provided the FDA has approved a petition that proposed filing such an application

The RLD Pentazocine Hydrochloride and Acetaminophen Tablets ANDA 74-699 by Watson Pharma Inc is an oral tablet product currently available as 25 mg650 mg The proposed drug product also is an oral tablet and will be available in the following strengths 125 mg325 mg and 25 mg325 mg Thus the petition is seeking a change in dosage strength (from 25 mg650 mg to 125 mg325 mg and 25 mg325 mg) from that of the RLD

F PIf - 2 ~LL~LL[icl cP LCSlachmanconsultantscom

lACHMAN CONSULTANT SERVICFSINC Westbury NY 11590

Division of Dockets Management Food and Drug Administration

June 72011 Page 2 of 3

The proposed change in strength for the acetaminophen component from 650 mg to 325 mg represents dosage strength that is consistent with the dosing recommendations of the RLDs approved labeling and is also consistent with the FDAs Safety Announcement of January 13 2011 regarding acetaminophenshycontaining prescription drug products [76 FR 2691] in that no single dosage unit may contain more than 325 mg of acetaminophen in a combination product The proposed dose of 325 mg acetaminophen is already recognized as safe and effective both as a single entity and as a constituent of combination products This is supported by the numerous applications already approved by the FDA with 325 mg of acetaminophen The proposed strength for the pentazocine component (reduced from 25 mg to 125 mg) has also previously been approved in combination with aspirin (see NDA 16-891 Talwinreg Compound) and shown to be safe and effective Additionally the RLD is a scored product allowing for half a tablet ie 125 mg325 mg to be given The strengths of the proposed product are also contemplated in the labeling of the RLD The current labeling of the RLD states

The usual adult dose is 1 tablet every 4 hours as needed for pain relief up to maximum of 6 tablets per day The usual duration of therapy is dependent upon the condition being treated but in any case should be reviewed regularly by the physician

Thus the 125 mg325 mg and 25 mg325 mg strengths of the proposed product will provide greater dosing flexibility to the healthcare practitioner so that the dose can be titrated according to the patients level of pain The dosing of the proposed product recommends also provides similar dosing guidelines

The usual adult dose is

125 mg325 mg - Two (2) tablets every 4 hours as needed for pain relief up to maximum of 12 tablets per day

25 mg325 mg - One (1) tablet every 4 hours as needed for pain relief up to maximum of 6 tablets per day

The usual duration of therapy is dependent upon the condition being treated but in any case should be reviewed regularly by the physician

The proposed product will be labeled in accordance with the approved labeling of the RLD product upon which this petition is based Any difference in the labeling will relate only to the difference in dosage strength and those differences that may be necessary because the products are made by different manufacturers or because of patent or exclusivity protection The uses indications warnings and directions for use will remain the same as that of the RLD Draft labeling for the proposed product is included in Attachment 3 and the approved labeling from the RLD is provided in Attachment 4

Therefore the petitioners request for the Commissioner to find that a change in dosage strength from 25 mg650 mg to 125 mg325 mg and 25 mg325 mg should raise no questions of safety or effectiveness and the Agency should approve the petition

c Environmentallmpact

The petitioner claims a categorical exclusion under 21 CFR 2531

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IACHMAN CONSULTANT SERVICES INC Division of Dockets Management Westbury NY 11S9() Food and Drug Administration


D Economic Impact

The petitioner does not believe that this is applicable in this case but will agree to provide such an analysis if requested by the Agency

E Certification

The undersigned certifies that to the best knowledge and belief of the undersigned this petition includes all information and views on which the petition relies and that it includes representative data and information known to the petitioner which are unfavorable to the petition

JJlpk

Attachments 1 Approved Drug Products with Therapeutic Equivalence Evaluations Electronic Orange Book listing accessed 51312011

2 Discontinued section of the Electronic Orange Book accessed 5312011 3 Draft Package Insert Labeling for the proposed product 4 Approved labeling for reference-listed drug

cc Johnny Young (OGD)

Talwinreg is a registered trademark of Sanofi Aventis

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Page 1 of2

From (516) 683-1681 Origin 10 RUEA II-Ii- Ship 0 07JUN11 Westbury Otke ~ AtNJ1t 10 lB

CAD 1879030111ET3130

_~~__~~~~SERVICl_S--=~==-i~~~liiiimifllll~111111111111111 SHIP TO 131118218 BllllEHDER Refll LCS DOCUtAENTS Division of Dockets Management Invoice II

Food amp Drugs Administration POll Deptll

DHHS HFAmiddot305 5830 Fishers Lane Room 1061

amp11 UC 11 lAD

5QDGtoctl)lEF8

After printing this label 1 Use the Print button on this page to print your label to your laser or Inkjet printer 2 Fold the printed page along the horizontal line 3 Place label in shipping pooch and affix nto your shipment $0 that tha barcode portion of the label can be read and scanned

Warning Use only the printed original label for shipping Using a photocopy of this label fur shipping purposes is fraudulent and could result in additional billing charges along w~h the cancellation of your FedEx account number

Use of thIS system CMsb1tltes your agreement to thii~seriilCiliiOOifitions Inthicurrent FedEXService Guide aVaiiable on iadegttcOmFedEle will not be responsible for any claim in _ of $100 per package whetner the result of loss damage deiay non-deiiverymisdelllleryor misinformation unless you dedare a higher value pay an additional charge document your actual loss and file a timely clalmUmitations found in the current FedEle Service Guide apply Your tight to recover from FedEllt for any loss including Intrinsic valueof the package loss of sales income intenes~ profi~ attorneys fees costs and other forms of damage whetner direct incidentalconsequential or special is limned to the greater 0($100 or the authorized declared value Recovery cannot exceed actual documented lossMaximum for items 01 extraordinary value is $500 eg Jewelry precious melais negotiable Instruments and other Items fisted in our ServiceGuide Written claims must be filed within strict time limits see current FedEle Service Guide

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LACHMANCONSULTANfSERVICFSINC Westbury NY 11590

ATTACHMENT 1

Active Ingredient Search Page 10f2

Quick Links Skip to main page content Skip to Search Skip to Topics Menu Skip to Section Content Menu Skip to Common Links

Orange Book Approved Drug Products with Therapeutic Equivalence Evaluations

Active Ingredient Search Results from OB_Rx table for query on pentazo

Appl No

TE Code

RLD Active Ingredient

Dosage Form Route

Strength Proprietary Name

Applicant

A076202 AB No ACETAMINOPHEN PENTAZOCINE HYDROCHLORIDE

TABLET ORAL

6S0MGEQ 2SMG BASE

ACETAMINOPHEN AND PENTAZOCINE HYDROCHLORIDE

GAVIS PHARMS

A074699 AB Yes ACETAMINOPHEN PENTAZOCINE HYDROCHLORIDE

TABLET ORAL

6S0MGEQ 2SMG BASE


WATSON LABS

A075735 AB No NALOXONE HYDROCHLORIDE PENTAZOCINE HYDROCHLORIDE

TABLET ORAL

EQ OSMG BASEEQ SOMG BASE

PENTAZOCINE AND NALOXONE HYDROCHLORIDE

GAVIS PHARMS


TABLET ORAL

EQ O5MG BASEEQ SOMG BASE

A074736 AB Yes NALOXONE HYDROCHLORIDE PENTAZOCINE HYDROCHLORIDE

TABLET ORAL


PENTAZOCINE AND NALOXONE HYDROCHLORIDES

RANBAXY


WATSON LABS

N016194 Yes PENTAZOCINE LACTATE

INJECTABLE INJECTION

EQ 30MG BASEML

TALWIN HOSPIRA

Return to Electronic Orange Book Home Page

FDACenter for Drug Evaluation and Research Office of Generic Drugs Division of Labeling and Program Support Update Frequency

httpwwwaccessdatafdagovscriptscderobdocstempaicfin 52712011

Page 2 of2Active Ingredient Search

Orange Book Data - Monthly

Generic Drug Product Infonnation amp Patent Information - Daily

Orange Book Data Updated Through April 2011

Patent and Generic Drug Product Data Last Updated May 26 2011

httpwwwaccessdatafdagovscriptscderobdocstempaicfm 52712011


ATTACHMENT 2

middot Active Ingredient Search Page I of I

Quick Links SkiD to main page content Skip to Search Skip to Topics Menu Skip to Section Content Menu Skip to Common Links


Active Ingredient Search Results from OB_Disc table for query on pentazocine

Appl No

Active Ingredient

Dosage Form Route


Applicant

N018458 ACETAMINOPHEN PENTAZOCINE HYDROCHLORIDE

TABLET ORAL

650MG EQ 25MG BASE

TALACEN SANOFI AVENTIS US

N016891 ASPIRIN PENTAZOCINE HYDROCHLORIDE

TABLET ORAL

325MGEQ 125MG BASE

TALWIN COMPOUND

SANOA AVENTIS US

N018733 NALOXONE HYDROCHLORIDE PENTAZOCINE HYDROCHLORIDE

TABLET ORAL

EQ 05MG BASEEQ 50MG BASE

TALWIN NX SANOFI AVENTIS US

N016732 PENTAZOCINE HYDROCHLORIDE TABLET ORAL

EQ 50MG BASE TALWIN 50 SANOA AVENTIS US




Generic Drug Product Information amp Patent Information - Daily


Patent and Generic Drug Product Data Last Updated May 272011


IACHMAN OONSULTANTSERVICFSINC Westbury NY 11590

ATTACHMENT 3

elv Pentazocine Hydrochloride and Acetaminophen Tablets 125 mg I 325 mg and 25 mg I 325 mg

DESCRIPTION

Pentazocine hydrochloride and acetaminophen tablets are a combination ofpentazocine hydrochloride USP equivalent to 125 mg or 25 mg base and acetaminophen USP 325 mg

Pentazocine is a member of the benzazocine series (also known as the benzomorphan series) Chemically pentazocine hydrochloride is (2R6RIIR )-123456-hexahydro-611shydimethyl-3-(3-methyl-2-butenyl)-26-methano-3-benzazocin-8-01 hydrochloride a white crystalline substance soluble in acidic aqueous solutions It has the following structural formula

bull Hel

Molecular Weight 32188

Chemically acetaminophen is 4-hydroxyacetanilide- It has the following structural formula

HO NHCOCH3


Pentazocine is an analgesic and acetaminophen is an analgesic and antipyretic

Each tablet 125 mgl325 mg tablet for oral administration contains 125 mg ofpentazocine as the hydrochloride and 325 mg of acetaminophen In addition each tablet contains the following inactive ingredients [to be determined]


Page 1


CLINICAL PHARMACOLOGY

Pentazocine hydrochloride and acetaminophen tablets are an analgesic possessing antipyretic actions Pentazocine is an analgesic with agonistantagonist action which when administered orally is approximately equivalent on a mg for mg basis in analgesic effect to codeine Acetaminophen is an analgesic and antipyretic

Onset of significant analgesia with pentazocine usually occurs between 15 and 30 minutes after oral administration and duration of action is usually three hours or longer Onset and duration of action and the degree of pain relief are related both to dose and the severity ofpretreatment pain Pentazocine weakly antagonizes the analgesic effects of morphine meperidine and phenazocine in addition it produces incomplete reversal of cardiovascular respiratory and behavioral depression induced by morphine and meperidine Pentazocine has about 1150 the antagonistic activity ofnalorphine It also has a sedative activity

Pentazocine is well absorbed from the gastrointestinal tract Plasma levels closely correspond to the onset duration and intensity of analgesia The time to mean peak concentration in 24 normal volunteers was 17 hours (range 05 to 4 hours) after oral administration and the mean plasma elimination half-life was 36 hours (range 15 to 10 hours)

The action of pentazocine is terminated for the most part by biotransformation in the liver with some free pentazocine excreted in the urine The products of the oxidation of the terminal methyl groups and glucuronide conjugates are excreted by the kidney Elimination of approximately 60 of the total dose occurs within 24 hours Pentazocine passes the placental barrier

Onset of significant analgesic and antipyretic activity of acetaminophen when administered orally occurs within 30 minutes and is maximal at approximately 2112 hours The pharmacological mode of action of acetaminophen is unknown at this time

Acetaminophen is rapidly and almost completely absorbed from the gastrointestinal tract In 24 normal volunteers the mean time to peak plasma concentration was 1 hour (range 025 to 3 hours) after oral administration and the mean plasma elimination half-life was 28 hours (range 2 to 4 hours)

The effect of pentazocine on acetaminophen plasma protein binding or vice versa has not been established For acetaminophen there is little or no plasma protein binding at normal therapeutic doses When toxic doses of acetaminophen are ingested and drug plasma levels exceed 90 mcglmL plasma binding may vary from 8 to 43

Page 2


Acetaminophen is conjugated in the liver with glucuronic acid and to a lesser extent with sulfuric acid Approximately 80 of acetaminophen is excreted in the urine after conjugation and about 3 is excreted unchanged The drug is also conjugated to a lesser extent with cysteine and

additionally metabolized by hydroxylation

If pentazocine hydrochloride and acetaminophen tablets are taken every 4 hours over an extended period of time accumulation ofpentazocine and to a lesser extent acetaminophen may

occur

INDICATIONS AND USAGE

Pentazocine Hydrochloride and Acetaminophen Tablets are indicated for the relief ofmild to moderate pain

CONTRAINDICATIONS

Pentazocine Hydrochloride and Acetaminophen Tablets should not be administered to patients who are hypersensitive to either pentazocine or acetaminophen

WARNINGS

Head Injury and Increased Intracranial Pressure As in the case ofother potent analgesics the potential of pentazocine for elevating cerebrospinal fluid pressure may be attributed to C02 retention due to the respiratory depressant effects of the drug These effects may be markedly exaggerated in the presence of head injury other intracranial lesions or a pre-existing increase in intracranial pressure Furthermore pentazocine can produce effects which may obscure the clinical course of patients with head injuries In such patients pentazocine hydrochloride and acetaminophen tablets must be used with extreme caution and only if its use is deemed essential

Acute eNS Manifestations Patients receiving therapeutic doses ofpentazocine have experienced hallucinations (usually visual) disorientation and confusion which have cleared spontaneously within a period of hours The mechanism of this reaction is not known Such patients should be closely observed and vital signs checked If the drug is reinstituted it should be done with caution since these acute CNS manifestations may recur There have been instances ofpsychological and physical dependence on parenteral pentazocine in patients with a history of drug abuse and rarely in patients without such a history (See DRUG ABUSE AND DEPENDENCE)

Due to the potential for increased CNS depressant effects alcohol should be used with caution in patients who are currently receiving pentazocine

Page 3


Pentazocine may precipitate opioid abstinence symptoms in patients receiving courses ofopiates

for pain relief

PRECAUTIONS

In prescribing pentazocine hydrochloride and acetaminophen tablets for chronic use the physician should take precautions to avoid increases in dose by the patient

Myocardial Infarction As with all drugs pentazocine hydrochloride and acetaminophen tablets should be used with caution in patients with myocardial infarction who have nausea or vomiting

Certain Respiratory Conditions Although respiratory depression has rarely been reported after oral administration of pentazocine the drug should be administered with caution to patients with respiratory depression

from any cause severely limited respiratory reserve severe bronchial asthma and other obstructive respiratory conditions or cyanosis

Impaired Renal or Hepatic Function Decreased metabolism of the drug by the liver in extensive liver disease may predispose to accentuation of side effects Although laboratory tests have not indicated that pentazocine causes or increases renal or hepatic impairment the drug should be administered with caution to patients with such impairment

Since acetaminophen is metabolized by the liver the question of the safety ofits use in the presence ofliver disease should be considered

Biliary Surgery Narcotic drug products are generally considered to elevate biliary tract pressure for varying periods following their administration Some evidence suggests that pentazocine may differ from other marketed narcotics in this respect (ie it causes little or no elevation in biliary tract pressures) The clinical significance of these findings however is not yet known

CNS Effect Caution should be used when pentazocine hydrochloride and acetaminophen tablets are administered to patients prone to seizures seizures have occurred in a few such patients in association with the use ofpentazocine although no cause and effect relationship has been established

Information for Patients

Page 4

elv Pentazocine Hydrochloride and Acetaminophen Tablets 125 mg 1325 mg and 25 mg 1325 mg

Since sedation dizziness and occasional euphoria have been noted ambulatory patients should be warned not to operate machinery drive cars or unnecessarily expose themselves to hazards Pentazocine may cause physical and psychological dependence when taken alone and may have additive CNS depressant properties when taken in combination with alcohol or other CNS

depressants

Drug Interactions Pentazocine is a mild narcotic antagonist Some patients previously given narcotics including methadone for the daily treatment ofnarcotic dependence have experienced withdrawal symptoms after receiving pentazocine

Carcinogenesis Mutagenesis Impairment of Fertility Carcinogenesis mutagenesis and impairment of fertility studies have not been done with this

combination product

Pentazocine when administered orally or parenterally had no adverse effect on either the reproductive capabilities or the course ofpregnancy in rabbits and rats Embryotoxic effects on

the fetuses were not shown

The daily administration of4 mglkg to 20 mglkg pentazocine subcutaneously to female rats during a 14 day pre-mating period and until the 13th day ofpregnancy did not have any adverse effects on the fertility rate

There is no evidence in long-term animal studies to demonstrate that pentazocine is carcinogenic

Pregnancy Category C Animal reproduction studies have not been conducted with pentazocine hydrochloride and acetaminophen tablets It is also not known whether pentazocine hydrochloride and acetaminophen tablets can cause fetal harm when administered to pregnant women or can affect reproduction capacity Pentazocine hydrochloride and acetaminophen tablets should be given to pregnant women only if clearly needed However animal reproduction studies with pentazocine have not demonstrated teratogenic or embryo toxic effects

Nonteratogenic Effects There has been no experience in this regard with the combination pentazocine and acetaminophen However there have been rare reports ofpossible abstinence syndromes in newborns after prolonged use ofpentazocine during pregnancy

Labor and Delivery

Page 5


Patients receiving pentazocine during labor have experienced no adverse effects other than those that occur with commonly used analgesics Pentazocine hydrochloride and acetaminophen tablets should be used with caution in women delivering premature infants The effect of pentazocine hydrochloride and acetaminophen tablets on the mother and fetus the duration of labor or delivery the possibility that forceps delivery or other intervention or resuscitation of the newborn may be necessary or the effect ofpentazocine hydrochloride and acetaminophen tablets on the later growth development and functional maturation of the child are unknown at the

present time

Nursing Mothers It is not known whether this drug is excreted in human milk Because many drugs are excreted in human milk caution should be exercised when pentazocine hydrochloride and acetaminophen

tablets are administered to a nursing woman

Pediatric Use Safety and effectiveness in pediatric patients below the age of 12 have not been established

Geriatric Use Clinical studies ofpentazocine hydrochloride and acetaminophen tablets did not include sufficient numbers ofsubjects 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 ofdecreased hepatic renal or cardiac function and of concomitant disease or other drug therapy

ADVERSE REACTIONS

Clinical experience with pentazocine hydrochloride and acetaminophen tablets has been insufficient to define all possible adverse reactions with this combination However reactions reported after oral administration ofpentazocine hydrochloride in 50 mg dosage include gastrointestinal nausea vomiting infrequently constipation and rarely abdominal distress anorexia diarrhea CNS effects dizziness lightheadedness hallucinations sedation euphoria headache confusion disorientation infrequently weakness disturbed dreams insomnia syncope visual blurring and focusing difficulty depression and rarely tremor irritability excitement tinnitus Autonomic sweating infrequently flushing and rarely chills Allergic infrequently rash and rarely urticaria edema of the face Cardiovascular infrequently decrease in blood pressure tachycardia Hematologic rarely depression ofwhite blood cells (especially granulocytes) which is usually reversible moderate transient eosinophilia Other rarely respiratory depression urinary retention paresthesia serious skin reactions including erythema

Page 6


multifonne Stevens-Johnson Syndrome toxic epidennal necrolysis and in one instance an

apparent anaphylactic reaction has been reported

Numerous clinical studies have shown that acetaminophen when taken in recommended doses is relatively free of adverse effects in most age groups even in the presence of a variety of

disease states A few cases of hypersensitivity to acetaminophen have been reported as manifested by skin rashes thrombocytopenic purpura rarely hemolytic anemia and agranulocytosis Occasional individuals respond to ordinary doses with nausea and vomiting and diarrhea

DRUG ABUSE AND DEPENDENCE

Controlled Substance The combination ofpentazocine hydrochloride and acetaminophen tablets is a Schedule N controlled substance

Abuse and Dependence There have been some reports ofdependence and ofwithdrawal symptoms with orally administered pentazocine There have been recorded instances of psychological and physical dependence in patients using parenteral pentazocine Abrupt discontinuance following the extended use of parenteral pentazocine has resulted in withdrawal symptoms Patients with a history ofdrug dependence should be under close supervision while receiving pentazocine hydrochloride and acetaminophen tablets There have been rare reports of possible abstinence syndromes in newborns after prolonged use ofpentazocine during pregnancy

Some tolerance to the analgesic and subjective effects ofpentazocine develops with frequent and repeated use

Drug addicts who are given closely spaced doses ofpentazocine (eg 60 mg to 90 mg every 4 hours) develop physical dependence which is demonstrated by abrupt withdrawal or by administration ofnaloxone The withdrawal symptoms exhibited after chronic doses ofmore than 500 mg ofpentazocine per day have similar characteristics but to a lesser degree ofopioid withdrawal and may be associated with drug seeking behavior

OVERDOSAGE

Manifestations Clinical experience with pentazocine hydrochloride and acetaminophen tablets has been insufficient to define the signs ofoverdosage with this product It may be assumed that signs and symptoms of pentazocine hydrochloride and acetaminophen tablets overdose would be a combination of those observed with pentazocine overdose and acetaminophen overdose

Page 7

elV Pentazocine Hydrochloride and Acetaminophen Tablets 125 mg I 325 mg and 25 mg I 325 mg

For pentazocine alone in single doses above 60 mg there have been reports of the occurrence of

nalorphine-like psychotomimetic effects such as anxiety nightmares strange thoughts and hallucinations Marked respiratory depression associated with increased blood pressure and

tachycardia have also resulted from excessive doses as have dizziness nausea vomiting

lethargy and paresthesias The respiratory depression is antagonized by naloxone (see

Treatment)

In acute acetaminophen overdosage dose-dependent potentially fatal hepatic necrosis is the most serious adverse effect Renal tubular necrosis hypoglycemic coma and thrombocytopenia

may also occur

In adults a single dose of 109 to 15 g (200 mglkg to 250 mglkg) ofacetaminophen may cause

hepatotoxicity A dose of25 g or more is potentially fatal The potential seriousness of the

intoxication may not be evident during the first two days ofacute acetaminophen poisoning

During the first 24 hours nausea vomiting anorexia and abdominal pain occur These may

persist for a week or more Liver injury may become evident the second day initial signs being

elevation of the serum transaminase and lactic dehydrogenase activity increased serum bilirubin concentration and prolongation ofprothrombin time Serum albumin concentration and alkaline

phosphatase activity may remain normal The hepatotoxicity may lead to encephalopathy coma and death Transient azotemia is evident in a majority ofpatients and acute renal failure occurs in

some

There have been reports ofglycosuria and impaired glucose tolerance but hypoglycemia may

also occur Metabolic acidosis and metabolic alkalosis have been reported Cerebral edema and nonspecific myocardial depression have also been noted Biopsy reveals centro lobular necrosis

with sparing of the periportal area The hepatic lesions are reversible over a period ofweeks or months in nonfatal cases

The severity of the liver injury can be determined by measurement of the plasma halftime of

acetaminophen during the first day ofacute poisoning If the halftime exceeds 4 hours hepatic

necrosis is likely and if the halftime is greater than 12 hours hepatic coma will probably occur

Only minimal liver damage has developed when the serum concentration was below 120

mcgmL at 12 hours after ingestion of the drug If serum bilirubin concentration is greater than 4 mgIOO mL during the first 5 days encephalopathy may occur

The seven day oral LD50 value for pentazocine hydrochloride and acetaminophen tablets in mice is 3570 mglkg

Page 8


Treatment Oxygen intravenous fluids vasopressors and other supportive measures should be employed as indicated Assisted or controlled ventilation should also be considered For respiratory depression due to overdosage or unusual sensitivity to pentazocine hydrochloride and acetaminophen tablets parenteral naloxone is a specific and effective antagonist

The toxic effects ofacetaminophen may be prevented or minimized by antidotal therapy with Nshyacetyl cysteine In order to obtain the best possible results N-acetylcysteine should be administered within approximately 16 hours of ingestion of the overdose For complete prescribing information for the approved use ofacetyl cysteine in the treatment of acetaminophen overdose see the package insert for acetylcysteine

Vigorous supportive therapy is required in severe intoxication Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication Induction ofvomiting or gastric lavage followed by oral administration ofactivated charcoal should be done in all cases

If hemodialysis can be initiated within the first 12 hours it is advocated for patients with a plasma acetaminophen concentration exceeding 120 mcgmL at 4 hours after ingestion ofthe drug

DOSAGE AND ADMINISTRATION

Adult The usual adult dose is


25 mg325 mg One (1) tablet every 4 hours as needed for pain relief up to maximum of 6 tablets per day

The usual duration of therapy is dependent upon the condition being treated but in any case should be reviewed regularly by the physician The effect ofmeals on the rate and extent of bioavailability ofboth pentazocine and acetaminophen has not been documented

HOW SUPPLIED

Pentazocine Hydrochloride and Acetaminophen Tablets 125 mg base325 mg are [to be determined]

Page 9


Pentazocine Hydrochloride and Acetaminophen Tablets 25 mg basel325 mg are [to be determined]

Store at controlled room temperature 15deg-30degC (59deg-86degF) [See USP]

Dispense in a tight light-resistant container as defined in the USP

Manufactured by Revised

Page 10

LACHMAN CONSULTANfSERVICFSINC Westbury NY 11590

ATTACHMENT 4

wwwlaehmanconsultantseom LCSlachmaneonsultantseom

Pentazocine HCI and Acetaminophen Tablets C-IV Rx only 30276-4 Page 1 of9

Pentazocine HcI And Acetaminophen (pentazocine hydrochloride and acetaminophen) Tablet

[Watson Laboratories Inc]

DESCRIPTION

Pentazocine hydrochloride and acetaminophen tablets are a combination of pentazocine hydrochloride USP equivalent to 25 mg base and acetaminophen USP 650 mg

Pentazocine is a member of the benzazocine series (also known as the benzomorphan series) Chemically pentazocine hydrochloride is (2R~6R~ 11 R)-123456-hexahydro-611shydimethyl-3-(3-methyl-2-butenyl)-26-methano-3-benzazocin-8-01 hydrochloride a white crystalline substance soluble in acidic aqueous solutions It has the following structural formula

bull HCI



HO NHCOCH 3

MoiecularWeight 15116

Pentazocine is an analgesiC and acetaminophen is an analgesic and antipyretic

Each tablet for oral administration contains 25 mg of pentazocine as the hydrochloride and 650 mg of acetaminophen In addition each tablet contains the following inactive ingredients colloidal silicon dioxide crospovidone DampC Yellow No 10 Aluminum Lake FDampC Blue No1 Aluminum Lake microcrystalline cellulose povidone pregelatinized starch sodium starch glycolate and stearic acid


Pentazocine hydrochloride and acetaminophen tablets are an analgesic possessing antipyretic actions

Pentazocine is an analgesiC with agonistantagonist action which when administered orally is

httpdailymednlrnnihgovdailymedfdafdaDrugXslcfmid=769amptype=display 52712011

middot Pentazocine HCI and Acetaminophen Tablets C-IV Rx only 30276-4 Page 2 of9

approximately equivalent on a mg for mg basis in analgesic effect to codeine

Acetaminophen is an analgesic and antipyretic

Onset of significant analgesia with pentazocine usually occurs between 15 and 30 minutes after oral administration and duration of action is usually three hours or longer Onset and duration of action and the degree of pain relief are related both to dose and the severity of pretreatment pain Pentazocine weakly antagonizes the analgesic effects of morphine meperidine and phenazocine in addition it produces incomplete reversal of cardiovascular respiratory and behavioral depression induced by morphine and meperidine Pentazocine has about 150 the antagonistic activity of nalorphine It also has a sedative activity



Onset of significant analgesic and antipyretiC activity of acetamino~hen when administered orally occurs within 30 minutes and is maximal at approximately 2 12 hours The pharmacological mode of action of acetaminophen is unknown at this time


The effect of pentazocine on acetaminophen plasma protein binding or vice versa has not been established For acetaminophen there is little or no plasma protein binding at normal therapeutic doses When toxic doses of acetaminophen are ingested and drug plasma levels exceed 90 mcgmL plasma binding may vary from 8 to 43

Acetaminophen is conjugated in the liver with glucuronic acid and to a lesser extent with sLilfuric acid Approximately 80 of acetaminophen is excreted in the urine after conjugation and about 3 is excreted unchanged The drug is also conjugated to a lesser extent with cysteine and additionally metabolized by hydroxylation

If pentazocine hydrochloride and acetaminophen tablets are taken every 4 hours over an extended period of time accumulation of pentazocine and to a lesser extent acetaminophen may occur


Pentazocine hydrochloride and acetaminophen tablets are indicated for the relief of mild to moderate pain

CONTRAINDICATIONS

Pentazocine hydrochloride and acetaminophen tablets should not be administered to patients who are hypersensitive to either pentazocine or acetaminophen

httpdailymednlmnihgovdailymedlfdalfdaDrugXslcfmid=769amptype=display 52712011


WARNINGS

Head Injury and Increased Intracranial Pressure As in the case of other potent analgesics the potential of pentazocine for elevating cerebrospinal fluid pressure may be attributed to C02 retention due to the respiratory depressant effects of the drug These effects may be markedly exaggerated in the presence of head injury other intracranial lesions or a pre-existing increase in intracranial pressure Furthermore pentazocine can produce effects which may obscure the clinical course of patients with head injuries In such patients pentazocine hydrochloride and acetaminophen tablets must be used with extreme caution and only if its use is deemed essential

Acute eNS Manifestations Patients receiving therapeutic doses of pentazocine have experienced hallucinations (usually visual) disorientation and confusion which have cleared spontaneously within a period of hours The mechanism of this reaction is not known Such patients should be closely observed and vital signs checked If the drug is reinstituted it should be done with caution since these acute CNS manifestations may recur

There have been instances of psychological and physical dependence on parenteral pentazocine in patients with a history of drug abuse and rarely in patients without such a history (See DRUG ABUSE AND DEPENDENCE)

Due to the potential for increased CNS depressant effects alcohol should be used with caution in patients who are currently receiving pentaZOCine

Pentazocine may precipitate opioid abstinence symptoms in patients receiving courses of opiates for pain relief

PRECAUTIONS

In prescribing pentazocine hydrochloride andacetaminophen tablets for chronic use the physician should take precautions to avoid increases in dose by the patient

Myocardial Infarction

As with all drugs pentazocine hydrochloride and acetaminophen tablets should be used with caution in patients with myocardial infarction who have nausea or vomiting

Certain Respiratory Conditions

Although respiratory depression has rarely been reported after oral administration of pentazocine the drug should be administered with caution to patients with respiratory depression from any cause severely limited respiratory reserve severe bronchial asthma and other obstructive respiratory conditions or cyanosis

Impaired Renal or Hepatic Function

Decreased metabolism of the drug by the liver in extensive liver disease may predispose to accentuation of side effects Although laboratory tests have not indicated that pentazocine causes or increases renal or hepatic impairment the drug should be administered with caution to patients with such impairment

Since acetaminophen is metabolized by the liver the question of the safety of its use in the presence of liver disease should be considered



Biliary Surgery

Narcotic drug products are generally considered to elevate biliary tract pressue for va~ing periods following their administration Some evidence suggests that pentazocine may differ from other marketed narcotics in this respect (Le it causes little or no elevation in biliary tract pressures) The clinical significance of these findings however is not yet known

CNS Effect

Caution should be used when pentazocine hydrochloride and acetaminophen tablets are administered to patients prone to seizures seizures have occurred in a few such patients in association with the use of pentazocine although no cause and effect relationship has been established

Infonnation for Patients

Since sedation dizziness and occasional euphoria have been noted ambulatory patients should be warned not to operate machinery drive cars or unnecessarily expose themselves to hazards Pentazocine may cause physical and psychological dependence when taken alone and may have additive CNS depressant properties when taken in combination with alcohol or other CNS depressants

Drug Interactions

Pentazocine is a mild narcotic antagonist Some patients previously given narcotics including methadone for the daily treatment of narcotic dependence have experienced withdrawal symptoms after receiving pentazocine

CarcinogenesiS Mutagenesis Impainnent of Fertility

Carcinogenesis mutagenesis and impairment of fertility studies have not been done with this combination product

Pentazocine when administered orally or parenterally had no adverse effect on either the reproductive capabilities or the course of pregnancy in rabbits and rats Embryotoxic effects on the fetuses were not shown

The daily administration of 4 mgkg to 20 mgkg pentazocine subcutaneously to female rats during a 14 day pre-mating period and until the 13th day of pregnancy did not have any adverse effects on the fertility rate


Pregnancy Category C

Animal reproduction studies have not been conducted with pentazocine hydrochloride and acetaminophen tablets It is also not known whether pentazOCine hydrochloride and acetaminophen tablets can cause fetal harm when administered to pregnant women or can affect reproduction capacity Pentazocine hydrochloride and acetaminophen tablets should be given to pregnant women only if clearly needed However animal reproduction studies with pentazocine have not demonstrated teratogenic or embryotoxic effects

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middot Pentazocine HCl and Acetaminophen Tablets C-IV Rx only 30276-4 Page 5 of9

Nonteratogenic Effects

There has been no experience in this regard with the combination pentazocine and acetaminophen However there have been rare reports of possible abstinence syndromes in newborns after prolonged use of pentazocine during pregnancy

Labor and Delivery

Patients receiving pentazocine during labor have experienced no adverse effects other than those that occur with commonly used analgesics Pentazocine hydrochloride and acetaminophen tablets should be used with caution in women delivering premature infants The effect of pentazocine hydrochloride and acetaminophen tablets on the mother and fetus the duration of labor or delivery the possibility that forceps delivery or other intervention or resuscitation of the newborn may be necessary or the effect of pentazocine hydrochloride and acetaminophen tablets on the later growth development and functional maturation of the child are unknown at the present time

Nursing Mothers

It is not known whether this drug is excreted in human milk Because many drugs are excreted in human milk caution should be exercised when pentazocine hydrochloride and acetaminophen tablets are administered to a nursing woman

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 have not been established

Geriatric Use

Clinical studies of pentazocine hydrochloride and acetaminophen tablets 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

ADVERSE REACTIONS

Clinical experience with pentazocine hydrochloride and acetaminophen tablets has been insufficient to define all possible adverse reactions with this combination However reactions reported after oral administration of pentazocine hydrochloride in 50 mg dosage include gastrOintestinal nausea vomiting infrequently constipation and rarely abdominal distress anorexia diarrhea CNS effects dizziness lightheadedness hallucinations sedation euphoria headache confusion disorientation infrequently weakness disturbed dreams insomnia syncope visual blurring and focusing difficulty depression and rarely tremor irritability excitement tinnitus Autonomic sweating infrequently flushing and rarely chills Allergic infrequently rash and rarely urticaria edema of the face Cardiovascular infrequently decrease in blood pressure tachycardia Hematologic rarely depression of white blood cells (especially granulocytes) which is usually reversible moderate transient eosinophilia Other rarely respiratory depression urinary retention parestheSia serious skin reactions including erythema multiforme Stevens-Johnson Syndrome toxic epidermal necrolysis and in one



instance an apparent anaphylactic reaction has been reported

Numerous clinical studies have shown that acetaminophen when taken in recommended doses is relatively free of adverse effects in most age groups even in the presence of a variety of disease states

A few cases of hypersensitivity to acetaminophen have been reported as manifested by skin rashes thrombocytopenic purpura rarely hemolytic anemia and agranulocytosis Occasional individuals respond to ordinary doses with nausea and vomiting and diarrhea


Controlled Substance The combination of pentazocine hydrochloride and acetaminophen tablets is a Schedule IV controlled substance

Abuse and Dependence There have been some reports of dependence and of withdrawal symptoms with orally administered pentazocine There have been recorded instances of psychological and physical dependence in patients using parenteral pentazocine Abrupt discontinuance following the extended use of parenteral pentazocine has resulted in withdrawal symptoms Patients with a history of drug dependence should be under close supervision while receiving pentazocine hydrochlOride and acetaminophen tablets There have been rare reports of possible abstinence syndromes in newborns after prolonged use of pentazocine during pregnancy

Some tolerance to the analgesic and subjective effects of pentazocine develops with frequent and repeated use

Drug addicts who are given closely spaced doses of pentazocine (eg 60 mg to 90 mg every 4 hours) develop physical dependence which is demonstrated by abrupt withdrawal or by administration of naloxone The withdrawal symptoms exhibited after chronic doses of more than 500 mg of pentazocine per day have similar characteristics but to a lesser degree of opioid withdrawal and may be associated with drug seeking behavior

OVERDOSAGE

Manifestations

Clinical experience with pentazocine hydrochloride and acetaminophen tablets has been insufficient to define the signs of overdosage with this product It may be assumed that signs and symptoms of pentazocine hydrochloride and acetaminophen tablets overdose would be a combination of those observed with pentazocine overdose and acetaminophen overdose

For pentazocine alone in single doses above 60 mg there have been reports of the occurrence of nalorphine-like psychotomimetic effects such as anxiety nightmares strange thoughts and hallucinations Marked respiratory depression associated with increased blood pressure and tachycardia have also resulted from excessive doses as have dizziness nausea vomiting lethargy and paresthesias The respiratory depression is antagonized by naloxone (see Treatment)

In acute acetaminophen overdosage dose-dependent potentially fatal hepatic necrosis is the most serious adverse effect Renal tubular necrosis hypoglycemic coma and thrombocytopenia may also occur

In adults a single dose of 10 g to 15 g (200 mgkg to 250 mgkg) of acetaminophen may cause hepatotoxicity A dose of 25 9 or more is potentially fatal The potential seriousness of the

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Pentazocine HCl and Acetaminophen Tablets C-IV Rx only 30276-4 Page 7 of9

intoxication may not be evident during the first two days of acute acetaminophen poisoning During the first 24 hours nausea vomiting anorexia and abdominal pain occur These may persist for a week or more Liver injury may become evident the second day initial signs being elevation of the serum transaminase and lactic dehydrogenase activity increased serum bilirubin concentration and prolongation of prothrombin time Serum albumin concentration and alkaline phosphatase activity may remain normal The hepatotoxicity may lead to encephalopathy coma and death Transient azotemia is evident in a majority of patients and acute renal failure occurs in some

There have been reports of glycosuria and impaired glucose tolerance but hypoglycemia may also occur Metabolic acidosis and metabolic alkalosis have been reported Cerebral edema and nonspecific myocardial depression have also been noted Biopsy reveals centrolobular necrosis with sparing of the periportal area The hepatic lesions are reversible over a period of weeks or months in nonfatal cases

The severity of the liver injury can be determined by measurement of the plasma halftime of acetaminophen during the first day of acute poisoning If the halftime exceeds 4 hours hepatic necrosis is likely and if the halftime is greater than 12 hours hepatic coma will probably occur Only minimal liver damage has developed when the serum concentration was below 120 mcgmL at 12 hours after ingestion of the drug If serum bilirubin concentration is greater than 4 mg100 mL during the first 5 days encephalopathy may occur

The seven day oral LDso value for pentazocine hydrochloride and acetaminophen tablets in mice is 3570 mgkg

Treatment

Oxygen intravenous fluids vasopressors and other supportive measures should be employed as indicated Assisted or controlled ventilation should also be considered For respiratory depression due to overdosage or unusual sensitivity to pentazocine hydrochloride and acetaminophen tablets parenteral naloxone is a specific and effective antagonist

The toxic effects of acetaminophen may be prevented or minimized by antidotal therapy with N-acetylcysteine In order to obtain the best possible results N-acetylcysteine should be administered within approximately 16 hours of ingestion of the overdose

For complete prescribing information for the approved use of acetylcysteine in the treatment of acetaminophen overdose see the package insert for acetylcysteine

Vigorous supportive therapy is required in severe intoxication Procedures to limit the continuing absorption of the drug must be readily performed since the hepatiC injury is dose dependent and occurs early in the course of intoxication Induction of vomiting or gastric lavage followed by oral administration of activated charcoal should be done in all cases

If hemodialysis can be initiated within the first 12 hours it is advocated for patients with a plasma acetaminophen concentration exceeding 120 mcgmL at 4 hours after ingestion of the drug


Adult The usual adult dose is 1 tablet every 4 hours as needed for pain relief up to maximum of 6 tablets per day

The usual duration of therapy is dependent upon the condition being treated but in any case should be reviewed regularly by the physiCian The effect of meals on the rate and extent of



bioavailability of both pentazocine and acetaminophen has not been documented

HOW SUPPLIED

Pentazocine Hydrochloride and Acetaminophen Tablets 25 mg base650 mg are light aqua capsule-shaped scored tablets debossed 396 to the left of the score 25 over 650 to the right of the score and WATSON on the reverse side supplied in bottles of 100

Store at controlled room temperature 15deg-30DC (59D-86degF) [See USP]


Watson Laboratories Inc Corona CA 92880 USA

30276-4 Revised February 2004

Pentazocine Hel and Acetaminophen (Pentazocine Hydrochloride and Acetaminophen)

PRODUCT INFO

Product Code 0591-0396 Dosage Form TABLET

Route Of Administration ORAL DEA Schedule CIV

INGREDIENTS

Name (Active Moiety) Type Strength

Pentazocine hydrochloride (Pentazocine) Active 25 MILLIGRAM In 1 TABLET

Acetaminophen (Acetaminophen) Active 650 MILLIGRAM In 1 TABLET

colloidial silicon dioxide Inactive

crospovidone

DampC Yellow No1 0 Aluminum Lake

FD amp C Blue No 1 Aluminum Lake

microcrystalline cellulose

povidone

pregelatinized starch



sodium starch gylcolate Inactive

stearic acid In~r~I~ -VIVI t)LUt (Llgnt aqua) core 2

Shape OVAL (Capsule-shaped) Symbol false

Imprint Code 39625650WATSON Coating false

Size 19mm

PACKAGING

NDC Package Description Multilevel Packaging 1 0591-0396-01 100 TABLET In 1 BOTTLE middotNone

Revised 052006

httpdailymednlmnihgovdailymedfdafdaDrugXslcfmid=769amptype=display 5272011

lACHMAN CONSULTANT SERVICFSINC Westbury NY 11590

Division of Dockets Management Food and Drug Administration


The proposed change in strength for the acetaminophen component from 650 mg to 325 mg represents dosage strength that is consistent with the dosing recommendations of the RLDs approved labeling and is also consistent with the FDAs Safety Announcement of January 13 2011 regarding acetaminophenshycontaining prescription drug products [76 FR 2691] in that no single dosage unit may contain more than 325 mg of acetaminophen in a combination product The proposed dose of 325 mg acetaminophen is already recognized as safe and effective both as a single entity and as a constituent of combination products This is supported by the numerous applications already approved by the FDA with 325 mg of acetaminophen The proposed strength for the pentazocine component (reduced from 25 mg to 125 mg) has also previously been approved in combination with aspirin (see NDA 16-891 Talwinreg Compound) and shown to be safe and effective Additionally the RLD is a scored product allowing for half a tablet ie 125 mg325 mg to be given The strengths of the proposed product are also contemplated in the labeling of the RLD The current labeling of the RLD states

The usual adult dose is 1 tablet every 4 hours as needed for pain relief up to maximum of 6 tablets per day The usual duration of therapy is dependent upon the condition being treated but in any case should be reviewed regularly by the physician

Thus the 125 mg325 mg and 25 mg325 mg strengths of the proposed product will provide greater dosing flexibility to the healthcare practitioner so that the dose can be titrated according to the patients level of pain The dosing of the proposed product recommends also provides similar dosing guidelines

The usual adult dose is


25 mg325 mg - One (1) tablet every 4 hours as needed for pain relief up to maximum of 6 tablets per day

The usual duration of therapy is dependent upon the condition being treated but in any case should be reviewed regularly by the physician

The proposed product will be labeled in accordance with the approved labeling of the RLD product upon which this petition is based Any difference in the labeling will relate only to the difference in dosage strength and those differences that may be necessary because the products are made by different manufacturers or because of patent or exclusivity protection The uses indications warnings and directions for use will remain the same as that of the RLD Draft labeling for the proposed product is included in Attachment 3 and the approved labeling from the RLD is provided in Attachment 4

Therefore the petitioners request for the Commissioner to find that a change in dosage strength from 25 mg650 mg to 125 mg325 mg and 25 mg325 mg should raise no questions of safety or effectiveness and the Agency should approve the petition

c Environmentallmpact

The petitioner claims a categorical exclusion under 21 CFR 2531

wwwlachmanconsultantscom LCSlachmanconaultantscom



D Economic Impact


E Certification


JJlpk






Page 1 of2


CAD 1879030111ET3130




amp11 UC 11 lAD

5QDGtoctl)lEF8






ATTACHMENT 1





Appl No

TE Code


Dosage Form Route


Applicant


TABLET ORAL

6S0MGEQ 2SMG BASE


GAVIS PHARMS


TABLET ORAL

6S0MGEQ 2SMG BASE


WATSON LABS


TABLET ORAL



GAVIS PHARMS


TABLET ORAL



TABLET ORAL



RANBAXY


WATSON LABS



EQ 30MG BASEML

TALWIN HOSPIRA











ATTACHMENT 2





Appl No

Active Ingredient

Dosage Form Route


Applicant


TABLET ORAL

650MG EQ 25MG BASE



TABLET ORAL

325MGEQ 125MG BASE

TALWIN COMPOUND

SANOA AVENTIS US


TABLET ORAL













ATTACHMENT 3


DESCRIPTION



bull Hel



HO NHCOCH3





Page 1










Page 2





occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006




D Economic Impact


E Certification


JJlpk






Page 1 of2


CAD 1879030111ET3130




amp11 UC 11 lAD

5QDGtoctl)lEF8






ATTACHMENT 1





Appl No

TE Code


Dosage Form Route


Applicant


TABLET ORAL

6S0MGEQ 2SMG BASE


GAVIS PHARMS


TABLET ORAL

6S0MGEQ 2SMG BASE


WATSON LABS


TABLET ORAL



GAVIS PHARMS


TABLET ORAL



TABLET ORAL



RANBAXY


WATSON LABS



EQ 30MG BASEML

TALWIN HOSPIRA











ATTACHMENT 2





Appl No

Active Ingredient

Dosage Form Route


Applicant


TABLET ORAL

650MG EQ 25MG BASE



TABLET ORAL

325MGEQ 125MG BASE

TALWIN COMPOUND

SANOA AVENTIS US


TABLET ORAL













ATTACHMENT 3


DESCRIPTION



bull Hel



HO NHCOCH3





Page 1










Page 2





occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006


Page 1 of2


CAD 1879030111ET3130




amp11 UC 11 lAD

5QDGtoctl)lEF8






ATTACHMENT 1





Appl No

TE Code


Dosage Form Route


Applicant


TABLET ORAL

6S0MGEQ 2SMG BASE


GAVIS PHARMS


TABLET ORAL

6S0MGEQ 2SMG BASE


WATSON LABS


TABLET ORAL



GAVIS PHARMS


TABLET ORAL



TABLET ORAL



RANBAXY


WATSON LABS



EQ 30MG BASEML

TALWIN HOSPIRA











ATTACHMENT 2





Appl No

Active Ingredient

Dosage Form Route


Applicant


TABLET ORAL

650MG EQ 25MG BASE



TABLET ORAL

325MGEQ 125MG BASE

TALWIN COMPOUND

SANOA AVENTIS US


TABLET ORAL













ATTACHMENT 3


DESCRIPTION



bull Hel



HO NHCOCH3





Page 1










Page 2





occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006



ATTACHMENT 1





Appl No

TE Code


Dosage Form Route


Applicant


TABLET ORAL

6S0MGEQ 2SMG BASE


GAVIS PHARMS


TABLET ORAL

6S0MGEQ 2SMG BASE


WATSON LABS


TABLET ORAL



GAVIS PHARMS


TABLET ORAL



TABLET ORAL



RANBAXY


WATSON LABS



EQ 30MG BASEML

TALWIN HOSPIRA











ATTACHMENT 2





Appl No

Active Ingredient

Dosage Form Route


Applicant


TABLET ORAL

650MG EQ 25MG BASE



TABLET ORAL

325MGEQ 125MG BASE

TALWIN COMPOUND

SANOA AVENTIS US


TABLET ORAL













ATTACHMENT 3


DESCRIPTION



bull Hel



HO NHCOCH3





Page 1










Page 2





occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006






Appl No

TE Code


Dosage Form Route


Applicant


TABLET ORAL

6S0MGEQ 2SMG BASE


GAVIS PHARMS


TABLET ORAL

6S0MGEQ 2SMG BASE


WATSON LABS


TABLET ORAL



GAVIS PHARMS


TABLET ORAL



TABLET ORAL



RANBAXY


WATSON LABS



EQ 30MG BASEML

TALWIN HOSPIRA











ATTACHMENT 2





Appl No

Active Ingredient

Dosage Form Route


Applicant


TABLET ORAL

650MG EQ 25MG BASE



TABLET ORAL

325MGEQ 125MG BASE

TALWIN COMPOUND

SANOA AVENTIS US


TABLET ORAL













ATTACHMENT 3


DESCRIPTION



bull Hel



HO NHCOCH3





Page 1










Page 2





occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006









ATTACHMENT 2





Appl No

Active Ingredient

Dosage Form Route


Applicant


TABLET ORAL

650MG EQ 25MG BASE



TABLET ORAL

325MGEQ 125MG BASE

TALWIN COMPOUND

SANOA AVENTIS US


TABLET ORAL













ATTACHMENT 3


DESCRIPTION



bull Hel



HO NHCOCH3





Page 1










Page 2





occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006



ATTACHMENT 2





Appl No

Active Ingredient

Dosage Form Route


Applicant


TABLET ORAL

650MG EQ 25MG BASE



TABLET ORAL

325MGEQ 125MG BASE

TALWIN COMPOUND

SANOA AVENTIS US


TABLET ORAL













ATTACHMENT 3


DESCRIPTION



bull Hel



HO NHCOCH3





Page 1










Page 2





occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006






Appl No

Active Ingredient

Dosage Form Route


Applicant


TABLET ORAL

650MG EQ 25MG BASE



TABLET ORAL

325MGEQ 125MG BASE

TALWIN COMPOUND

SANOA AVENTIS US


TABLET ORAL













ATTACHMENT 3


DESCRIPTION



bull Hel



HO NHCOCH3





Page 1










Page 2





occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006



ATTACHMENT 3


DESCRIPTION



bull Hel



HO NHCOCH3





Page 1










Page 2





occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006



DESCRIPTION



bull Hel



HO NHCOCH3





Page 1










Page 2





occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006











Page 2





occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006






occur



CONTRAINDICATIONS


WARNINGS




Page 3



for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006




for pain relief

PRECAUTIONS










Page 4



depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006




depressants



combination product







Labor and Delivery

Page 5



present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006




present time





ADVERSE REACTIONS


Page 6











OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006












OVERDOSAGE


Page 7






Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006







Treatment)


may also occur








some










Page 8











HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006












HOW SUPPLIED


Page 9






Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006







Page 10


ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006



ATTACHMENT 4





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006





DESCRIPTION



bull HCI



HO NHCOCH 3





















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006















CONTRAINDICATIONS




WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006



WARNINGS






PRECAUTIONS











Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006



Biliary Surgery


CNS Effect




Drug Interactions













Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006





Labor and Delivery


Nursing Mothers


Pediatric Use


Geriatric Use


ADVERSE REACTIONS












OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006











OVERDOSAGE

Manifestations











Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006







Treatment












HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006




HOW SUPPLIED







PRODUCT INFO



INGREDIENTS





crospovidone




povidone








Size 19mm

PACKAGING


Revised 052006







Size 19mm

PACKAGING


Revised 052006


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CONSliLTANTS TO THE PHARMACEUTICAL AND … 2011/2011P-0459.01.pdfMay 27, 2011 · CONSliLTANTS TO THE PHARMACEUTICAL AND ALLIED INDUSTRIES . ... Pentazocine Hydrochloride and ... PENTAZOCINE