NDA 20-732
`NDA 20-733
`
`Page 7
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`(CIII)
`SUBOXONE
`(buprenorphine HCl and naloxone HCl dihydrate sublingual tablets)
`
`(C III)
`SUBUTEX
`(buprenorphine HCI sublingual tablets)
`
`Rx only
`
`Under the Drug Addiction Treatment Act of2000 (DATA) codified at 21 U.S.C.
`823(g), prescription use of this product in the treatment of opioid dependence is
`limited to physicians who meet certain qualifying requirements, and have notified the
`Secretary of Health and Human Services (HHS) of their intent to prescribe this
`product for the treatment of opioid dependence.
`
`DESCRIPTION
`
`SUBOXONE sublingual tablets contain buprenorphine HCl and naloxone HCl dihydrate at a
`ratio of 4:1 buprenorphine: naloxone (ratio of free bases).
`
`SUBUTEX sublingual tablets contain buprenorphine HCl.
`
`Buprenorphine is a partial agoni st at the mu-opioid receptor and an antagonist at the kappa-
`opioid receptor. Naloxone is an antagonist at the mu-opioid receptor.
`
`Buprenorphine is a Schedule III narcotic under the Controlled Substances Act.
`
`Buprenorphine hydrochloride is a white powder, weakly acidic with limited solubility in
`water (l7mg/mL). Chemically, buprenorphine is 17-(cyclopropylmethyl)-0L -(l,l-
`dimethylethyl)-4, 5-epoxy-l8, l9-dihydro-3-hydroXy-6-methoXy- or -methyl-6, 14-
`ethenomorphinan-7-methanol, hydrochloride [5oL, 70c(S)]-. Buprenorphine hydrochloride has
`the molecular formula C29 H41 N04 HCl and the molecular weight is 504.10.
`
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`NDA 20-732
`NDA 20-733
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`Page 8
`
`STRUCTURAL FORMULA OF BUPRENORPHINE
`
`HC1
`
`HO
`
`
`
`-—-CH3
`
`. ‘
`
`C(CH3)3
`
`CH3O
`
`HO
`
`Naloxone hydrochloride is a white to slightly off-white powder and is soluble in water, in
`dilute acids and in strong alkali. Chemically, naloxone is l7—Allyl—4,5 ot —epoxy—3, 14-
`dihydroxymorphinan-6-one hydrochloride. Naloxone hydrochloride has the molecular
`formula C19 H21NO4 HCl .2H2 O and the molecular weight is 399.87.
`
`STRUCTURAL FORMULA OF NALOXONE
`
`
`
`.HCl
`
`SUBOXONE is an uncoated hexagonal orange tablet intended for sublingual administration.
`It is available in two dosage strengths, 2mg buprenorphine with O.5mg naloxone, and 8mg
`buprenorphine with 2mg naloxone free bases. Each tablet also contains lactose, mannitol,
`cornstarch, povidone K3 0, citric acid, sodium citrate, FD&C Yellow No.6 color, magnesium
`stearate, and the tablets also contain Acesulfame K sweetener and a lemon / lime flavor.
`
`SUBUTEX is an uncoated oval white tablet intended for sublingual administration. It is
`available in two dosage strengths, 21ng buprenorphine and Sing buprenorphine free base.
`Each tablet also contains lactose, mannitol, cornstarch, povidone K30, citric acid, sodium
`citrate and magnesium stearate.
`
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`NDA 20-732
`NDA 20-733
`
`Page 9
`
`CLINICAL PHARMACOLOGY
`
`Subjective Effects.‘
`Comparisons of buprenorphine with full agonists such as methadone and hydromorphone
`suggest that sublingual buprenorphine produces typical opioid agonist effects which are
`limited by a ceiling effect.
`
`In non-dependent subjects, acute sublingual doses of SUBOXONE tablets produced opioid
`agonist effects, which reached a maximum between doses of 8 mg and 16mg of SUBUTEX.
`The effects of 16mg SUBOXONE were similar to those produced by 16mg SUBUTEX
`(buprenorphine alone).
`
`Opioid agonist ceiling effects were also observed in a double-blind, parallel group, dose
`ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32
`mg), placebo, and a full agonist control at various doses. The treatments were given in
`ascending dose order at intervals of at least one week to 16 opioid-experienced, non-
`dependent subjects. Both drugs produced typical opioid agonist effects. For all the measures
`for which the drugs produced an effect, buprenorphine produced a dose-related response but,
`in each case, there was a dose that produced no further effect.
`In contrast, the highest dose of
`the full agonist control always produced the greatest effects. Agonist objective rating scores
`remained elevated for the higher doses of buprenorphine (8-32 mg) longer than for the lower
`doses and did not return to baseline until 48 hours after drug administrations. The onset of
`effects appeared more rapidly with buprenorphine than with the full agonist control, with
`most doses nearing peak effect after 100 minutes for buprenorphine compared to 150 minutes
`for the full agonist control.
`
`Physiologic Ejfects:
`Buprenorphine in intravenous (2mg, 4mg, 8mg, 12mg and l6 mg) and sublingual (l2mg)
`doses has been administered to non-dependent subjects to examine cardiovascular, respiratory
`and subjective effects at doses comparable to those used for treatment of opioid dependence.
`Compared with placebo, there were no statistically significant differences among any of the
`treatment conditions for blood pressure, heart rate, respiratory rate, 02 saturation or skin
`temperature across time. Systolic BP was higher in the 8 mg group than placebo (3 hour AUC
`values). Minimum and maximum effects were similar across all treatments. Subjects remained
`responsive to low voice and responded to computer prompts. Some subjects showed
`irritability, but no other changes were observed.
`
`The respiratory effects of sublingual buprenorphine were compared with the effects of
`methadone in a double-blind, parallel group, dose ranging comparison of single doses of
`buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (l 5, 30, 45, or
`60 mg) in non-dependent, opioid-experienced volunteers. In this study, hypoventilation not
`requiring medical intervention was reported more frequently after buprenorphine doses of 4
`mg and higher than after methadone. Both drugs decreased 02 saturation to the same degree.
`
`Effect of Naloxone:
`Physiologic and subjective effects following acute sublingual administration of SUBOXONE
`and SUBUTEX tablets were similar at equivalent dose levels of buprenorphine. Naloxone, in
`
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`NDA 20-732
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`
`Page 10
`
`the SUBOXONE formulation, had no clinically significant effect when administered by the
`sublingual route, although blood levels of the drug were measurable. SUBOXONE, when
`administered sublingually even to an opioid-dependent population, was recognized as an
`opioid agonist, whereas when administered intramuscularly, combinations of buprenorphine
`with naloxone produced opioid antagonist actions similar to naloxone. In methadone-
`maintained patients and heroin-dependent subjects, intravenous administration of
`buprenorphine/naloxone combinations precipitated opioid withdrawal and was perceived as
`unpleasant and dysphoric. In morphine-stabilized subjects, intravenously administered
`combinations of buprenorphine with naloxone produced opioid antagonist and withdrawal
`effects that were ratio-dependent; the most intense withdrawal effects were produced by 2:1
`and 4:1 ratios, less intense by an 8:1 ratio. SUBOXONE tablets contain buprenorphine with
`naloxone at a ratio of 4: 1.
`
`Pharmacokinetics:
`
`Absorption:
`Plasma levels of buprenorphine increased with the sublingual dose of SUBUTEX and
`SUBOXONE, and plasma levels of naloxone increased with the sublingual dose of
`SUBOXONE (Table 1). There was a wide inter-patient variability in the sublingual absorption
`of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and
`AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of
`4 to 16 mg), although the increase was not directly dose-proportional.
`
`Naloxone did not affect the pharmacokinetics of buprenorphine and both SUBUTEX and
`SUBOXONE deliver similar plasma concentrations of buprenorphine. The levels of naloxone
`were too low to assess dose-proportionality. At the three naloxone doses of 1 mg, 2 mg, and 4
`mg, levels above the limit of quantitation (0.05 ng/1nL) were not detected beyond 2 hours in
`seven of eight subjects.
`In one individual, at the 4mg dose, the last measurable concentration
`was at 8 hours. Within each subject (for most of the subjects), across the doses there was a
`trend toward an increase in naloxone concentrations with increase in dose. Mean peak
`naloxone levels ranged from 0.11 to O.28ng/ml in the dose range of 1-4 mg.
`
`Table 1. Pharmacokinetic parameters of buprenorphine after the administration of 4 mg, 8mg,
`and 16 mg Suboxone® doses and 16mg Subutex® dose (mean (%CV)).
`
`Pharmacokinetic Parameter
`
`Suboxone® Suboxone®
`
`Suboxone® Subutex
`
`Cmax,11g/ITIL
`
`4 In
`
`1.84 (39)
`
`_
`
`3.0 (51)
`
`16 In
`
`16 m
`
`5.95 (38)
`
`32.63 (25)
`
`AUC0_43,hour*ng/mL
`
`12.52(35)
`
`2o.22(43)
`
`34.89(33)
`
`Distribution:
`
`Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.
`
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`
`\Ialoxone is approximately 45% protein bound, primarily to albumin.
`
`Metabolism:
`
`Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The
`‘\1-dealkylation pathway is mediated by cytochrome P-450 3A4 isozyme. Norbuprenorphine,
`an active metabolite, can further undergo glucuronidation.
`
`\Ialoxone undergoes direct glucuronidation to naloxone 3-glucuronide as well as N-
`dealkylation, and reduction of the 6-oxo group.
`
`Elimination:
`
`A mass balance study of buprenorphine showed complete recovery of radiolabel in urine
`(30%) and feces (69%) collected up to 11 days after dosing. Almost all of the dose was
`accounted for in terms of buprenorphine, norbuprenorphine, and two unidentified
`buprenorphine metabolites. In urine, most of buprenorphine and norbuprenorphine was
`conjugated (buprenorphine, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and
`11% conjugated). In feces, almost all of the buprenorphine and norbuprenorphine were free
`(buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2%
`conjugated).
`
`Buprenorphine has a mean elimination half-life from plasma of 37 h.
`
`Naloxone has a mean elimination half-life from plasma of 1.1 h.
`
`Special Populations:
`Hepatic Disease:
`The effect of hepatic impairment on the pharrnacokinetics of buprenorphine and naloxone is
`unknown. Since both drugs are extensively metabolized, the plasma levels will be expected
`to be higher in patients with moderate and severe hepatic impairment. However, it is not
`known whether both drugs are affected to the same degree. Therefore, in patients with
`hepatic impairment dosage should be adjusted and patients should be observed for symptoms
`of precipitated opioid withdrawal.
`
`Renal Disease:
`
`No differences in buprenorphine pharrnacokinetics were observed between 9 dialysis-
`dependent and 6 normal patients following intravenous administration of 0.3mg
`buprenorphine.
`
`The effects of renal failure on naloxone pharrnacokinetics are unknown.
`
`Drug-drug interactions.-
`CYP 3A4 Inhibitors and Inducers: A pharrnacokinetic interaction study of ketoconazole (400
`mg/day), a potent inhibitor of CYP 3A4, in 12 patients stabilized on SUBOXONE [8mg (n=1)
`or 12mg (n=5) or 16mg (n=6)] resulted in increases in buprenorphine mean Cmax values
`(from 4.3 to 9.8, 6.3 to 14.4 and 9.0 to 17.1) and mean AUC values (from 30.9 to 46.9, 41.9 to
`83.2 and 52.3 to 120) respectively. Subjects receiving SUBUTEX or SUBOXONE should be
`
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`
`NDA 20-732
`NDA 20-733
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`Page 12
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`closely monitored and may require dose-reduction if inhibitors of CYP 3A4 such as azole
`antifungal agents (e.g. ketoconazole), macrolide antibiotics (e.g., erythromycin) and HIV
`protease inhibitors (e. g. ritonavir, indinavir and saquinavir) are co-administered. The
`interaction of buprenorphine with CYP 3A4 inducers has not been investigated; therefore it is
`recommended that patients receiving SUBUTEX or SUBOXONE should be closely
`monitored if inducers of CYP 3A4 (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin)
`are co-administered (SEE WARNINGS).
`
`CLINICAL STUDIES
`
`Clinical data on the safety and efficacy of SUBOXONE and SUBUTEX are derived from
`studies of buprenorphine sublingual tablet formulations, with and without naloxone, and from
`studies of sublingual administration of a more bioavailable ethanolic solution of
`buprenorphine.
`
`SUBOXONE tablets have been studied in 575 patients, SUBUTEX tablets in 1834 patients
`and buprenorphine sublingual solutions in 2470 patients. A total of 1270 females have
`received buprenorphine in clinical trials. Dosing recommendations are based on data from one
`trial of both tablet formulations and two trials of the ethanolic solution. All trials used
`
`buprenorphine in conjunction with psychosocial counseling as part of a comprehensive
`addiction treatment program. There have been no clinical studies conducted to assess the
`efficacy of buprenorphine as the only component of treatment.
`
`In a double blind placebo- and active controlled study, 326 heroin-addicted subj ects were
`randomly assigned to either SUBOXONE 16 mg per day, 16 mg SUBUTEX per day or
`placebo tablets. For subjects randomized to either active treatment, dosing began with one 8
`mg tablet of SUBUTEX on Day 1, followed by 16 mg (two 8 mg tablets) of SUBUTEX on
`Day 2. On Day 3, those randomized to receive SUBOXONE were switched to the
`combination tablet. Subjects randomized to placebo received one placebo tablet on Day 1 and
`two placebo tablets per day thereafter for four weeks. Subjects were seen daily in the clinic
`(Monday through Friday) for dosing and efficacy assessments. Take-home doses were
`provided for weekends. Subjects were instructed to hold the medication under the tongue for
`approximately 5 to 10 minutes until completely dissolved. Subjects received one hour of
`individual counseling per week and a single session of HIV education. The primary study
`comparison was to assess the efficacy of SUBUTEX and SUBOXONE individually against
`placebo. The percentage of thrice—weekly urine samples that were negative for non—study
`opioids was statistically higher for both SUBUTEX and SUBOXONE, than for placebo.
`
`In a double-blind, double-dummy, parallel-group study comparing buprenorphine ethanolic
`solution to a full agonist active control, 162 subjects were randomized to receive the ethanolic
`sublingual solution of buprenorphine at 8 mg/day (a dose which is roughly comparable to a
`dose of 12 mg/day of SUBUTEX or SUBOXONE), or two relatively low doses of active
`control, one of which was low enough to serve as an alternative to placebo, during a 3-10 day
`induction phase, a 16-week maintenance phase and a 7-week detoxification phase.
`Buprenorphine was titrated to maintenance dose by Day 3; active control doses were titrated
`more gradually.
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`Page 13
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`Maintenance dosing continued through Week 17, and then medications were tapered by
`approximately 20-3 0% per week over Weeks 18-24, with placebo dosing for the last two
`weeks. Subjects received individual and/or group counseling weekly.
`
`Based on retention in treatment and the percentage of thrice-weekly urine samples negative
`for non-study opioids, buprenorphine was more effective than the low dose of the control, in
`keeping heroin addicts in treatment and in reducing their use of opioids while in treatment.
`The effectiveness of buprenorphine, 8 mg per day was similar to that of the moderate active
`control dose, but equivalence was not demonstrated.
`
`In a dose-controlled, double-blind, parallel-group, 16-week study, 731 subjects were
`randomized to receive one of four doses of buprenorphine ethanolic solution. Buprenorphine
`was titrated to maintenance doses over 1-4 days (Table 2) and continued for 16 weeks.
`Subjects received at least one session of AIDS education and additional counseling ranging
`from one hour per month to one hour per week, depending on site.
`
`Table 2. Doses of Sublingual Buprenorphine Solution used for Induction in a Double-
`Blind Dose Ranging Study
`
`Induction Dose
`
`Maintenance
`
`Target Dose of
`
`Buprenorphine
`
`1:
`
`16m
`
`2m
`
`
`
`Day2
`1m
`4mg
`4mg
`4m
`g
`
`dose
`
`8m
`
`16m
`
`*Sublingual solution. Doses in this table cannot necessarily be delivered in tablet form, but for comparison purposes:
`2 mg solution would be roughly equivalent to 3 n1g tablet
`4 mg solution would be roughly equivalent to 6 mg tablet
`8 mg solution would be roughly equivalent to 12 mg tablet
`16 mg solution would be roughly equivalent to 24 111g tablet
`
`Based on retention in treatment and the percentage of thrice-weekly urine samples negative
`for non-study opioids, the three highest tested doses were superior to the 1mg dose.
`Therefore, this study showed that a range of buprenorphine doses may be effective. The 1mg
`dose of buprenorphine sublingual solution can be considered to be somewhat lower than a 2
`mg tablet dose. The other doses used in the study encompass a range of tablet doses from
`approximately 6 mg to approximately 24 mg.
`
`INDICATIONS AND USAGE
`
`SUBOXONE and SUBUTEX are indicated for the treatment of opioid dependence.
`
`CONTRAINDICATIONS
`
`SUBOXONE and SUBUTEX should not be administered to patients who have been shown to
`be hypersensitive to buprenorphine, and SUBOXONE should not be administered to patients
`who have been shown to be hypersensitive to naloxone.
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`Page 14
`
`WARNINGS
`
`Respiratory Depression.‘
`Significant respiratory depression has been associated with buprenorphine, particularly by the
`intravenous route. A number of deaths have occurred when addicts have intravenously
`misused buprenorphine, usually with benzodiazepines concomitantly. Deaths have also been
`reported in association with concomitant administration of buprenorphine with other
`depressants such as alcohol or other opioids. Patients should be warned of the potential
`danger of the self-administration of benzodiazepines or other depressants while under
`treatment with SUBUTEX or SUBOXONE.
`
`IN THE CASE OF OVERDOSE, THE PRIMARY MANAGEMENT SHOULD BE THE RE-
`
`ESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL
`
`ASSISTANCE OF RESPIRATION, IF REQUIRED. NALOXONE MAY NOT BE
`EFFECTIVE IN REVERSING ANY RESPIRATORY DEPRESSION PRODUCED BY
`
`BUPRENORPHINE.
`
`SUBOXONE and SUBUTEX should be used with caution in patients with compromised
`respiratory function (e. g., chronic obstructive pulmonary disease, cor pulmonale, decreased
`respiratory reserve, hypoxia, hypercapnia, or pre—exi sting respiratory depression).
`
`CNS Depression:
`Patients receiving buprenorphine in the presence of other narcotic analgesics, general
`anesthetics, benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics or other
`CNS depressants (including alcohol) may exhibit increased CNS depression. When such
`combined therapy is contemplated, reduction of the dose of one or both agents should be
`considered.
`
`Dependence:
`Buprenorphine is a partial agoni st at the mu—opiate receptor and chronic administration
`produces dependence of the opioid type, characterized by withdrawal upon abrupt
`discontinuation or rapid taper. The withdrawal syndrome is milder than seen with full
`agonists, and may be delayed in onset
`
`Hepatitis, hepatic events:
`Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in the addict
`population receiving buprenorphine both in clinical trials and in post—marl<eting adverse event
`reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in
`hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal
`syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver
`enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of
`other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a
`causative or contributory role. In other cases, insufficient data were available to determine the
`etiology of the abnormality. The possibility exists that buprenorphine had a causative or
`contributory role in the development of the hepatic abnormality in some cases. Measurements
`of liver function tests prior to initiation of treatment is recommended to establish a baseline.
`Periodic monitoring of liver function tests during treatment is also recommended. A
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`
`biological and etiological evaluation is recommended when a hepatic event is suspected.
`Depending on the case, the drug should be carefully discontinued to prevent withdrawal
`symptoms and a return to illicit drug use, and strict monitoring of the patient should be
`initiated.
`
`Allergic Reactions:
`Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in
`clinical trials and in the post-marketing experience. The most common signs and symptoms
`include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and
`anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a
`contraindication to Subutex or Suboxone use. A history of hypersensitivity to naloxone is a
`contraindication to Suboxone use.
`
`Use in Ambulatory Patients.‘
`SUBOXONE and SUBUTEX may impair the mental or physical abilities required for the
`performance of potentially dangerous tasks such as driving a car or operating machinery,
`especially during drug induction and dose adjustment. Patients should be cautioned about
`operating hazardous machinery, including automobiles, until they are reasonably certain that
`buprenorphine therapy does not adversely affect their ability to engage in such activities.
`Like other opioids, SUBOXONE and SUBUTEX may produce orthostatic hypotension in
`ambulatory patients.
`
`Head Injury and Increased Intracranial Pressure.‘
`SUBOXONE and SUBUTEX, like other potent opioids, may elevate cerebrospinal fluid
`pressure and should be used with caution in patients with head injury, intracranial lesions and
`other circumstances where cerebrospinal pressure may be increased. SUBOXONE and
`SUBUTEX can produce miosis and changes in the level of consciousness that may interfere
`with patient evaluation.
`
`Opioid withdrawal effects.‘
`Because it contains naloxone, SUBOXONE is highly likely to produce marked and intense
`withdrawal symptoms if misused parenterally by individuals dependent on opioid agonists
`such as heroin, morphine, or methadone. Sublingually, SUBOXONE may cause opioid
`withdrawal symptoms in such persons if administered before the agonist effects of the opioid
`have subsided.
`
`PRECAUTIONS
`
`General:
`
`SUBOXONE and SUBUTEX should be administered with caution in elderly or debilitated
`patients and those with severe impairment of hepatic, pulmonary, or renal function;
`myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS
`depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute
`alcoholism; delirium tremens; or kyphoscoliosis.
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`
`The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is
`unknown. Since both drugs are extensively metabolized, the plasma levels will be expected
`to be higher in patients with moderate and severe hepatic impairment. However, it is not
`known whether both drugs are affected to the same degree. Therefore, dosage should be
`adjusted and patients should be watched for symptoms of precipitated opioid withdrawal.
`
`Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and
`thus should be administered with caution to patients with dysfunction of the biliary tract.
`
`As with other mu-opioid receptor agonists, the administration of SUBOXONE or SUBUTEX
`may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
`
`Drug Interactions:
`Buprenorphine is metabolized to norbuprenorphine by cytochrome CYP 3A4. Because CYP
`3A4 inhibitors may increase plasma concentrations of buprenorphine, patients already on
`CYP 3A4 inhibitors such as azole antifungals (e. g. ketoconazole), macrolide antibiotics (e.g.
`erythromycin), and HIV protease inhibitors (e. g. ritonavir, indinavir and saquinavir) should
`have their dose of SUBUTEX or SUBOXONE adjusted.
`
`Based on anecdotal reports, there may be an interaction between buprenorphine and
`benzodiazepines. There have been a number of reports in the post—marketing experience of
`coma and death associated with the concomitant intravenous misuse of buprenorphine and
`benzodiazepines by addicts. In many of these cases, buprenorphine was misused by self-
`injection of crushed SUBUTEX tablets. SUBUTEX and SUBOXONE should be prescribed
`with caution to patients on benzodiazepines or other drugs that act on the central nervous
`system, regardless of whether these drugs are taken on the advice of a physician or are taken
`as drugs of abuse. Patients should be warned of the potential danger of the intravenous self-
`administration of benzodiazepines while under treatment with SUBOXONE or SUBUTEX.
`
`Information for Patients:
`Patients should inform their family members that, in the event of emergency, the treating
`physician or emergency room staff should be informed that the patient is physically dependent
`on narcotics and that the patient is being treated with SUBOXONE or SUBUTEX.
`
`Patients should be cautioned that a serious overdose and death may occur if benzodiazepines,
`sedatives, tranquilizers, antidepressants, or alcohol are taken at the same time as SUBOXONE
`or SUBUTEX.
`
`SUBOXONE and SUBUTEX may impair the mental or physical abilities required for the
`performance of potentially dangerous tasks such as driving a car or operating machinery,
`especially during drug induction and dose adjustment. Patients should be cautioned about
`operating hazardous machinery, including automobiles, until they are reasonably certain that
`buprenorphine therapy does not adversely affect their ability to engage in such activities.
`Like other opioids, SUBOXONE and SUBUTEX may produce orthostatic hypotension in
`ambulatory patients.
`
`TEVA EXHIBIT 1008
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`
`
`TEVA EXHIBIT 1008
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`NDA 20-732
`NDA 20-733
`
`Page 17
`
`Patients should consult their physician if other prescription medications are currently being
`used or are prescribed for future use.
`
`Carcinogenesis, Mutagenesis and Impairment of Fertilizjy:
`Carcinogenicity.‘ Carcinogenicity data on SUBOXONE are not available. Carcinogenicity
`studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice.
`Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day
`(estimated exposure was approximately 0.4, 3 and 35 times the recommended human daily
`sublingual dose of 16 mg on a mg/m2 basis) for 27 months. Statistically significant dose-
`related increases in testicular interstitial (Leydig’s) cell tumors occurred, according to the
`trend test adjusted for survival. Pair-wise comparison of the high dose against control failed
`to show statistical significance. In an 86-week study in CD-1 mice, buprenorphine was not
`carcinogenic at dietary doses up to 100 mg/kg/day (estimated exposure was approximately 30
`times the recommended human daily sublingual dose of 16 mg on a mg/m2 basis).
`
`ZI/Iatagenicity.‘
`SUBOXONE: The 4:1 combination of buprenorphine and naloxone was not mutagenic in a
`bacterial mutation assay (Ames test) using four strains of S. iyphimurium and two strains of E.
`coli. The combination was not clastogenic in an in vitro cytogenetic assay in human
`lymphocytes, or in an intravenous micronucleus test in the rat.
`
`SUBUTEX: Buprenorphine was studied in a series of tests utilizing gene, chromosome, and
`DNA interactions in both prokaryotic and eukaryotic systems. Results were negative in yeast
`(Saccharomyces cerevisiae) for recombinant, gene convertant, or forward mutations; negative
`in Bacillus subiilis “rec” assay, negative for clastogenicity in CHO cells, Chinese hamster
`bone marrow and sperinatogonia cells, and negative in the mouse lymphoma L5178Y assay.
`Results were equivocal in the Ames test: negative in studies in two laboratories, but positive
`for frame shift mutation at a high dose (Smg/plate) in a third study. Results were positive in
`the Green—Tweets (E. coli) survival test, positive in a DNA synthesis inhibition (DSI) test
`with testicular tissue from mice, for both in vivo and in vitro incorporation of [3H]thymidine,
`and positive in unscheduled DNA synthesis (UDS) test using testicular cells from mice.
`
`Impairment ofFertility.‘
`SUBOXONE: Dietary administration of SUBOXONE in the rat at dose levels of 500 ppm or
`greater (equivalent to approximately 47 mg/kg/day or greater; estimated exposure was
`approximately 28 times the recommended human daily sublingual dose of 16 mg on a mg/m2
`basis) produced a reduction in fertility demonstrated by reduced female conception rates. A
`dietary dose of 100 ppm (equivalent to approximately 10 mg/kg/day; estimated exposure was
`approximately 6 times the recommended human daily sublingual dose of 16 mg on a mg/m2
`basis) had no adverse effect on fertility.
`
`SUBUTEX: Reproduction studies of buprenorphine in rats demonstrated no evidence of
`impaired fertility at daily oral doses up to 80mg/kg/day (estimated exposure was
`approximately 50 times the recommended human daily sublingual dose of 16 mg on a mg/m2
`basis) or up to 5mg/kg/day im or sc (estimated exposure was approximately 3 times the
`recommended human daily sublingual dose of 16 mg on a mg/m2 basis).
`
`TEVA EXHIBIT 1008
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`
`
`TEVA EXHIBIT 1008
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`NDA 20-732
`NDA 20-733
`
`Page 18
`
`Pregnancy:
`Pregnancy Category C.'
`Teratogenic eflects:
`SUBOXONE: Effects on embryo-fetal development were studied in Sprague-Dawley rats and
`Russian white rabbits following oral (1:1) and intramuscular (3 :2) administration of mixtures
`of buprenorphine and naloxone. Following oral administration to rats and rabbits, no
`teratogenic effects were observed at doses up to 250 mg/kg/day and 40 mg/kg/day,
`respectively (estimated exposure was approximately 150 times and 50 times, respectively, the
`recommended human daily sublingual dose of 16 mg on a mg/m2 basis). No definitive drug-
`related teratogenic effects were observed in rats and rabbits at intramuscular doses up to 30
`mg/kg/day (estimated exposure was approximately 20 times and 35 times, respectively, the
`recommended human daily dose of 16 mg on a mg/m2 basis). Acephalus was observed in one
`rabbit fetus from the low—dose group and omphacele was observed in two rabbit fetuses from
`the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose
`group. Following oral administration to the rat, dose-related post-implantation losses,
`evidenced by increases in the numbers of early resorptions with consequent reductions in the
`numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure
`was approximately 6 times the recommended human daily sublingual dose of 16 mg on a
`mg/m2 basis). In the rabbit, increased post-implantation losses occurred at an oral dose of 40
`mg/kg/day. Following intramuscular administration in the rat and the rabbit, post-implantation
`losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30
`mg/kg/day.
`
`SUB UTEX: Buprenorphine was not teratogenic in rats or rabbits after im or sc doses up to 5
`mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the
`recommended human daily sublingual dose of 16 mg on a mg/m2 basis), after iv doses up to
`0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respective