Introduction
`
`
`
`SCIENTIFIC DISCUSSION
`
`1.
`
`Drug addiction is a worldwide problem of which opioid dependence, notably heroin addiction, is a
`major component. Most addicts inject drugs, quite often with dirty or shared syringes and needles and
`this behaviour is linked directly with the transmission of human immunodeficiency virus (HIV) and
`the hepatitis viruses. A key aim of treatment programs for opioid drug dependence is to stop the
`subjects from injecting drugs. Substitution is the treatment approach for opioid dependence in which
`street heroin of unknown strength and purity is replaced with a pharmaceutical grade opioid with a
`longer duration of action, such as buprenorphine.
`
`Buprenorphine is a well-known substance available in several European countries for the treatment of
`severe pain. For the treatment of opioid dependence it was first approved in 1995 (France) and is
`currently available in most European countries. Buprenorphine has lower intrinsic activity than
`methadone and other full agonists, produces less sedation and cognitive impairment, and has a ceiling
`on potential depressant effects, even if injected, particularly on cardiac and respiratory functions.
`Sublingual buprenorphine (marketed as Buprenorphine alone) is an established substitution treatment
`for opiate abuse, but there has been some diversion to the intravenous route because buprenorphine
`produces a moderate opiate agonist effect. Thus, in the opinion of the applicant, there is a need for a
`formulation of buprenorphine that has low potential for intravenous misuse.
`
`SUBOXONE is a fixed combination product for chronic substitution therapy in opiate dependence
`consisting of buprenorphine and naloxone formulated
`into a sublingual
`tablet containing
`buprenorphine and naloxone in the ratio 4:1 of the bases.
`The claimed indication for SUBOXONE is substitution treatment for opioid drug dependence,
`within a framework of medical, social and psychological treatment. The intention of the
`naloxone component is to deter intravenous misuse. As requested by the CHMP, treatment is
`intended for use in adults and adolescents over 15 years of age who have agreed to be treated for
`addiction.
`The product is intended as a “take home” medication presented in two strengths:
`1. Buprenorphine 8 mg + naloxone 2 mg sublingual tablet
`2. Buprenorphine 2 mg + naloxone 0.5 mg sublingual tablet.
`
`The combination of an opioid antagonist with a potent µ-opioid analgesic is an established strategy for
`reducing the potential for intravenous misuse. Naloxone is a well-known opioid antagonist. As a
`mono-substance it is indicated for the treatment of opioid-overdosage or –intoxication. When
`administered in usual doses to patients who have not recently received opioids, naloxone exerts little
`or no pharmacologic effect. In patients who have received large doses of opioids, naloxone
`antagonises most of the effects of the opioid. The addition of naloxone to buprenorphine is intended to
`render the product less abusable by deterring intravenous injection.
`
`2. Quality aspects
`
`Introduction
`
`Suboxone is presented as sublingual tablets containing a fixed dose combination of buprenorphine
`hydrochloride and naloxone hydrochloride dihydrate, at a ratio of 4:1, with respect to the free bases.
`Suboxone is available in two strengths:
`• 2 mg / 0.5 mg tablets containing 2.16 mg buprenorphine hydrochloride (equivalent to 2 mg
`buprenorphine base) and 0.61 mg naloxone hydrochloride dihydrate (equivalent to 0.5 mg
`naloxone base).
`
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`TEVA EXHIBIT 1011
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`

`
`• 8 mg / 2 mg containing 8.64 mg buprenorphine hydrochloride (equivalent to 8 mg
`buprenorphine base) and 2.44 mg naloxone hydrochloride dihydrate (equivalent to 2 mg
`naloxone base).
`The excipients used in this formulation are lactose monohydrate, mannitol, maize starch, povidone
`K30, citric acid anhydrous granular, sodium citrate, natural lemon and lime flavour, acesulfame
`potassium and magnesium stearate. Suboxone is administered via the sublingual route and is packed in
`nylon/aluminium/PVC blister packs containing either 7 or 28 tablets.
`
`Active Substance 1. (Buprenorphine hydrochloride)
`
`Buprenorphine hydrochloride is an established active substance and the subject of a monograph in the
`Ph. Eur.
`Buprenorphine hydrochloride is designated chemically as (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-
`3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol
`hydrochloride
`and its chemical structure is as follows:
`
`
`
`
`Buprenorphine hydrochloride is a white or almost white, crystalline powder, sparingly soluble in
`water, freely soluble in methanol, soluble in alcohol, practically insoluble in cyclohexane.
`Buprenorphine has several chiral centres and it is therefore optically active.
`The potential for polymorphism was investigated using powder X-Ray diffraction and Differential
`Scanning Calorimetry (DSC) techniques. The results showed that there is no evidence for
`polymorphism.
`
` •
`
` Manufacture
`Buprenorphine hydrochloride is synthesized from thebaine. The structure has been confirmed by
`elemental analysis, spectroscopic analysis (UV, IR, NMR and MS) and X-Ray crystallography. The
`stereochemistry of the intermediates and the final active substance was investigated using X-ray
`crystallography and NMR spectroscopy. The absolute configuration was confirmed at different stages
`during the synthesis.
`
` •
`
` Specification
`The specification of the active substance includes physical description, visual inspection of the
`appearance in solution, assay by titration and by HPLC, specific optical rotation, acidity or alkalinity
`and related substances (HPLC). Additional tests performed are as follows: control for water content
`using the Karl Fisher method and residue on ignition, residual solvent, ionic chloride and particle size.
`
`The analytical methods used were those described in the PhEur. Monograph, one major exception
`being the determination of related substances. The HPLC method for determination of related
`impurities uses specific impurity markers. It allows detection and quantitation of the five major
`impurities specified, whereas using the method described in the Ph. Eur. only two of the impurities can
`be detected. In addition, the acceptance criteria set for each specified impurity is more stringent than
`the limits mentioned in Ph. Eur. monograph. The maximum limit for total related impurities is also
`
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`

`
`more stringent than that mentioned in the current Ph. Eur. Monograph. All analytical methods have
`been validated according to the ICH guideline on “Validation of Analytical methods”.
`
`Batch analysis data was provided for 23 batches of buprenorphine hydrochloride manufactured
`following the proposed synthetic method. The results showed that the active substance can be
`reproducibly manufactured.
`
`
` Stability
`The stability of buprenorphine hydrochloride was investigated in 3-production scale batches stored in
`the proposed packaging according to the ICH guideline. Stability studies were performed under long
`term and intermediate ICH conditions for 156 weeks, and accelerated ICH conditions for 52 weeks.
`An additional study was performed using a larger scale production batch. In this study the stability
`studies were performed under long-term and intermediate conditions for 52 weeks and accelerated
`conditions for 39 weeks. The results obtained demonstrate that buprenorphine hydrochloride remains
`physically and chemically stable for 52 week at long-term and intermediate conditions and 26 weeks
`at accelerated conditions.
`
`The data provided is sufficient to confirm the proposed re-test period.
`
`Active Substance 2. (Naloxone hydrochloride dihydrate)
`
`Naloxone hydrochloride dihydrate is an established active substance and the subject of a monograph
`in the Ph. Eur. Naloxone hydrochloride dihydrate is designated chemically as Morphinan-6-one, 4,5-
`epoxy-3, 14-dihydroxy-17-(2-propenyl)-, hydrochloride, (5α)-dihydrate. Its chemical structure is as
`follows:
`
` •
`
`2
`
`HO
`
`3
`
`
`
`4
`
`O
`
`5
`
`12
`
`15
`
`13
`
`14
`
`1
`
`11
`
`10
`16
`
`
`19
`
`18
`
`N
`
`9
`OH
`
`17
`
`6
`
`O
`
`7
`
`8
`
`
`
`Naloxone hydrochloride dihydrate is a white or almost white crystalline powder, hygroscopic, soluble
`in water and alcohol, practically insoluble in ether. The pKa of Naloxone hydrochloride dihydrate is
`7.94 at 20oC and the melting point is 200-205oC.
`
` •
`
` Manufacture
`Naloxone hydrochloride is synthesised from noroxymorphone. The assigned structure of naloxone
`hydrochloride dihydrate is supported by the evidence of IR spectrophotometry, and by 1H-NMR and
`13C-NMR spectrometry.
`
`Naloxone hydrochloride dihydrate contains four chiral centres, all of which are already present in the
`starting material of the synthesis, noroxymorphone, which is derived from natural opiates.
`
`The possibility of polymorphism was investigated by standard techniques. The results showed that all
`batches exhibited the same morphic form.
`
` •
`
` Specification
`Naloxone hydrochloride dihydrate is tested for compliance with both PhEur. and USP monographs by
`the active substance manufacturer. These tests include physical description, identification by IR, TLC
`and chloride, specific optical rotation, loss on drying, Noroxymorphone hydrochloride and other
`impurities by TLC, chloride content, appearance of solution, acidity or alkalinity, related substances
`by HPLC, water content, sulphated ash and assay by titration. The specification also includes some
`additional non-pharmacopoeial tests (a stability-indicating HPLC method for assay and related
`
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`TEVA EXHIBIT 1011
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`

`
`substances, UV identification, sieve analysis and the melting range of naloxone base). The stability-
`indicating HPLC assay has been fully validated and was shown to have satisfactory linearity,
`precision, accuracy and ruggedness. The peak area of naloxone decreases and degradation products are
`observed in samples exposed to stress conditions, confirming that the assay is stability-indicating.
`
`Five batches of naloxone hydrochloride were manufactured using the proposed synthetic method. The
`results indicate that every batch complied with the limits for related substances.
`
` •
`
` Stability
`The stability of naloxone hydrochloride was investigated in 12 batches stored in the proposed
`packaging according to the ICH guideline. Stability studies were performed under long term,
`intermediate and accelerated ICH conditions for up to 60 months. No marked evidence of instability
`was revealed under any of the storage conditions and the proposed re-test period appears to be
`justified on the basis of the stability data presented.
`
`Medicinal Product
`
` •
`
` Pharmaceutical Development
`Suboxone was developed in order to deliver a similar dose of buprenorphine compared to
`buprenorphine alone tablets (medicinal product containing buprenorphine that is authorised in the EU
`for the treatment of opioid addiction), but reducing the potential for intravenous abuse. Naloxone, an
`opiate antagonist, has poor bioavailability when administered by the sublingual route and
`consequently when Suboxone is taken sublingually it shows only the required effects of
`buprenorphine and delivers the same performance as an equivalent dose of buprenorphine alone
`tablets. However, if abused intravenously by an opiate-dependent subject, the antagonist effects of
`naloxone become apparent first as intense withdrawal symptoms followed by the attenuated agonist
`effects of buprenorphine.
`
`Therefore the Suboxone formulation is closely based on the formulation of buprenorphine alone
`sublingual tablets but with naloxone added to reduce the potential for abuse by the intravenous route.
`A buprenorphine to naloxone ratio of 4:1 contains sufficient naloxone to produce opiate antagonist
`effects following intra-venous administration, but does not impair the effectiveness of buprenorphine
`when the mixture is taken by the sublingual route.
`
`The excipients used in Suboxone are qualitatively and quantitatively identical to those used in the
`existing buprenorphine alone sublingual tablets, i.e., lactose monohydrate, mannitol, maize starch,
`povidone K30, citric acid anhydrous, sodium citrate and magnesium stearate. Acesulfame potassium
`and natural lemon and lime flavour (sweetener and flavouring agents, respectively) were included to
`disguise the bitter taste of naloxone. The content of lactose monohydrate was reduced slightly in order
`to maintain identical compression weights. All excipients have been widely used in commercial
`pharmaceutical dosage forms or as food additives. Except for the natural lemon and lime flavour all
`excipients comply with the specification of the Ph. Eur. Natural lemon and lime flavour is a natural
`flavouring, which complies the requirements of directive 88/388/EEC (as amended) on flavourings for
`use in food. Certificates of analysis have been provided for all excipients.
`
` •
`
` •
`
` Adventitious Agents
`Lactose monohydrate is the only excipient of animal origin. However, it is prepared from bovine milk
`suitable for human consumption, which is sourced from healthy animals. Magnesium stearate is of
`vegetable origin.
`
` Manufacture of the Product
`The manufacturing process of the finished product comprises standard mixing, wet granulation and
`compression techniques. Process parameter ranges (sieve sizes, mixing times and speed, drying time
`and temperature) were described for each step of the manufacturing process. Validation studies
`involved the preparation of 3 full-scale batches of the tablet blend. Each of the batches was then sub-
`divided into two sub-lots for the preparation of tablets of both strengths, i.e., 2 mg/0.5 mg tablets and
`8 mg/2 mg tablets. An additional full-scale batch of each tablet strength was manufactured. All eight
`batches complied with final product specification. From the evidence of the process validation studies
`
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`provided, it can be concluded that the process is capable of consistently producing batches of the
`required quality.
`
`
` Product Specification
`The product specifications include methods for appearance, identification (buprenorphine and
`naloxone) by HPLC and TLC, assay and content uniformity (buprenorphine and naloxone) by HPLC,
`dissolution of buprenorphine and dissolution of naloxone, disintegration time, buprenorphine
`degradation products, naloxone degradation products, water content and microbiological integrity.
`
`The drug product specifications have been justified and all methods of analysis have been described
`and adequately validated.
`
` •
`
` •
`
` Stability of the Product
`Stability data on three batches of each strength of Suboxone sublingual tablets (8 mg / 2 mg and 2 mg
`/ 0.5 mg) packaged under a nitrogen atmosphere was provided. The studies were performed under
`long-term, intermediate, and accelerated conditions. The parameters evaluated during these studies
`were those mentioned in the shelf-life specification, except for two minor deviations. Analytical
`results up to 156 weeks were presented. All tests remained within specification for 156 weeks at
`25°C/60% RH. The key shelf-life limiting parameter appeared to be disintegration time. There is
`evidence of a time-dependent increase but all samples stored at complied with the specification for
`156 weeks.
`
`
`Based on the available stability data, the proposed shelf life and storage conditions, as stated in the
`SPC, are acceptable.
`
`Discussion on chemical, pharmaceutical and biological aspects
`
`Information on development, manufacture and control of the drug substances and drug product has
`been presented in a satisfactory manner. The results of test carried out indicate satisfactory consistency
`and uniformity of important product quality characteristics, and these in turn lead to the conclusion
`that the product should have a satisfactory and uniform performance in the clinic.
`
`
`
`
`Introduction
`Most of the preclinical studies were conducted in accordance with good laboratory practice
`regulations. Some studies have been performed prior to the introduction of GLP regulation and are not
`GLP-compliant. Since both of the active ingredients are established substances the documentation for
`pharmacology consists of published literature plus study reports with the combination of the active
`ingredients.
`
` •
`
` Pharmacology
`Buprenorphine is a semisynthetic, highly lipophilic opioid derived from thebaine with a 25 -30 fold
`higher analgesic potency as compared to morphine and a longer lasting effect. It is a partial agonist at
`the µ- and an antagonist at the κ-opioid receptor subtype. It dissociates very slowly from opioid
`receptors (t½ 166 min vs. 7 min for fentanyl) and is, once bound, hardly displaced by naloxone,
`however, prior treatment with naloxone can prevent e.g. respiratory depression. It is able to substitute
`for other opioids such as heroin but provides only moderate opiate agonist effects and a low degree of
`physical dependence. Being a partial µ-receptor agonist it may cause symptoms of abstinence in
`patients treated with µ-receptor agonists (e.g. morphine) and restricts its own analgesic effects once a
`maximum is reached, resulting in a bell-shaped dose response curve. When treatment with
`buprenorphine is discontinued withdrawal signs are generally mild due to slow dissociation from the
`µ-receptor and concomitant adaptive processes.
`
`Naloxone is the N-allyl derivative of oxymorphone. It has antagonistic effects at µ, δ- and κ-opioid
`receptors and is currently marketed in injectable form for the complete or partial reversal of opiate
`effects or for the suspected acute opiate overdose. When given alone, hardly any effect is observed
`
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`Non-clinical aspects
`
`3.
`
` •
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`hinting at a low endogenous opioidergic tonus. Because of its almost complete first pass metabolism,
`naloxone administered orally or sublingually is not expected to exert antagonistic activity. No
`documents dealing with the pharmacodynamics of naloxone were submitted.
`
`Receptor Binding:
`In the review presented in association with this application the receptor binding affinities of
`buprenorphine and naloxone for narcotic receptors are outline in the following table.
`
`Table: In vitro receptor-binding affinities for Buprenorphine and Naloxone.
`Drug
`Ki (nM)
`Kappa (κ)
`
`Buprenorphine
`1.1
`Naloxone
`12
`
`Mu (µ)
`0.77
`1.2
`
`Delta (δ)
`2.2
`19
`
`Sigma (σ)
`>100000
`>1000000
`
`Ratio (σ/κ)
`>91000
`>83000
`
` •
`
` Primary pharmacodynamics
`In vivo studies have been carried out in order to examine the interaction of both substances as regards
`effects (antinociception), precipitation of withdrawal in morphine dependent rats, drug discrimination
`in rats and avoidance behaviour in monkeys.
`
`Antinociceptive effects of buprenorphine and morphine given alone or in combination with naloxone
`(subcutaneous route) were measured in the rat tail pressure test: the results provided some evidence
`that buprenorphine is antagonised by naloxone, although less readily than morphine.
`
`Buprenorphine and naloxone administered intraperitoneally to precipitate withdrawal signs in
`morphine-dependent rats suggest that buprenorphine did not affect the ability of naloxone to
`precipitate signs of opiate withdrawal.
`
`To test whether buprenorphine plus naloxone mixtures are still perceived like buprenorphine alone, a
`drug discrimination study was performed. Male rats with about 300 g b.w. were trained to discriminate
`between subcutaneous (s.c.) injection of buprenorphine 0.03 mg/kg in an operant chamber with two
`levers, where repeated pressure of the correct lever (10x) resulted in the delivery of a food pellet. 30
`min after application the pattern of lever pressing was recorded. No food reward was given during
`generalisation trials. Generalisation was considered to have occurred, if the percent responding on the
`relevant lever was 70 % or more. Responding to the buprenorphine-appropriate lever was 97 %
`following buprenorphine, 2 % following saline and 8 % following naloxone. Addition of naloxone
`0.002, 0.01 and 0.02 mg/kg to buprenorphine resulted in 93 %, 59 % and 23 % buprenorphine lever
`pressing, respectively. It is concluded that buprenorphine combined with naloxone in a ratio 3:2 is not
`probable to be a narcotic cue to support opiate misuse.
`
`Negative reinforcing properties of naloxone were studied in the non-dependent rhesus monkey:
`scheduled infusions of naloxone (1-100 µg/kg/inf.) and of buprenorphine (250 µg/kg/inf.) generated
`drug avoidance behavior in the non-dependent rhesus monkey under a continuous avoidance-escape
`paradigm. Pentazocine (1-100 µg/kg/inf.) codeine, (1-100 µg/kg/inf. and tilidine (1-250 µg/kg/inf.)
`were ineffective. Addition of varying doses of naloxone to scheduled infusions of codeine, tilidine,
`and pentazocine generated avoidance behavior not present with scheduled infusions of these opioids
`alone. The naloxone doses necessary for generation of avoidance behavior were low with the agonists
`codeine and tilidine, higher with the weak antagonist pentazocine, and highest with the strong
`antagonist buprenorphine.
`Monkeys were trained to avoid conditioned noxious stimuli. Subsequently, avoidance behaviour was
`extinguished and scheduled intravenous infusions of drugs were tested for their ability to re-introduce
`avoidance behaviour. Comparable to nalorphine, the opioid antagonist naloxone exerted negative
`reinforcing properties. The agonists codeine and tilidine had no effects on the behaviour of their own,
`as had the mixed agonist/antagonist pentazocine, while buprenorphine had a weak negative reinforcing
`effect only in the highest dose tested. Naloxone was added to equi-analgesic doses of the test
`compounds. Low doses were needed to induce negative reinforcement in the presence of codeine and
`tilidine, somewhat higher doses in the presence of pentazocine and high doses in the presence of
`buprenorphine.
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`
`
`Overall, where interaction between buprenorphine and naloxone was shown, the routes of
`administration used in the pharmacology studies may have limited relevance to the proposed clinical
`route of administration (sublingual) and the ratios chosen in these studies (3:1) do not reflect the
`proposed clinical ratio of 4:1. Thus ‘proof of principle’ that co-administration of naloxone will prevent
`intravenous misuse of buprenorphine has further to be derived from clinical studies and clinical
`evidence.
`
`Buprenorphine and norbuprenorphine did not displace peripheral [3H]PK 11195 binding and central
`[3H]flunitrazepam binding, indicating lack of interaction with the GABAA-receptors.
`
`Diazepam and flunitrazepam have no significant affinity to human µ- and δ- opioid receptors and poor
`affinity to human κ-opioid receptors.
`
` •
`
` Secondary pharmacodynamics
`In order to look for blood compatibility (protein precipitating and haemolytic effects) of the
`combination of buprenorphine and naloxone 3: 2, the powdered product was dissolved in 5 % aqueous
`glucose or was diluted from a pre-prepared solution and added to citrated blood withdrawn from
`beagle dogs. The slight haemolysis observed with therapeutic concentration is not likely to be of
`clinical significance in the case that intravenous abuse of the product should occur.
`
` •
`
` •
`
` Safety pharmacology programme
`No new studies were submitted. Due to the well-known pharmacology of the single substances and
`since no adverse interactions between these to substances are expected this procedure is acceptable.
`
` Pharmacodynamic drug interactions
`No unexpected pharmacodynamic drug interactions have been identified.
`
`Pharmacokinetics
`Pharmacokinetics of both buprenorphine and naloxone are well known. Buprenorphine is sufficiently
`absorbed following sublingual administration and is eliminated with a long half-life. Naloxone has a
`low oral bioavailability and and is rapidly eliminated when given parenterally.
`In a preclinical study it is shown, that co-administration of buprenorphine and naloxone had little or
`no effect on their individual pharmacokinetic profiles following administration by i.v. or i.m or by oral
`dosing.
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`
`
`Table. Results of single dose pharmacokinetic studies in rats and dogs with 3H-buprenorphine and 3H-naloxone
`alone or in combination with non-radiolabelled naloxone or buprenorphine respectively.
`3H-Buprenorphine
`3H Buprenorphine +
`3H-Naloxone
`R
`S
`O
`Naloxone
`P
`U
`E
`AUC (0-8
`T
`C
`hr)
`E
`I
`ng/g h
`
`E
`S
`Rat
`
`3H-Naloxone +
`Buprenorphine
`AUC
`Cmax
`Cmax
`Plasm
`Brain
`(0-8 hr)
`a ng/g
`ng/
`ng/g h
`equiv
`
`690
`760
`26
`Auc (0-
`24 hr)
`ng/g h
`20
`Auc
`(0-96
`hr)
`ng/g h
`25.5
`5.5
`
`1736
`1850
`5853
`
`
`*
`
`
`*
`*
`
`Dog
`
`
`
` •
`
`Cmax
`Plasm
`a ng/g
`
`AUC (0-8
`hr)
`ng/g h
`
`i.v.
`i.m.
`p.o.
`
`
`1442
`892
`571
`
`
`i.v.
`
`
`788
`
`
`1799
`2248
`188
`Auc (0-24
`hr) ng/g
`h
`65
`Auc (0-
`96 hr)
`ng/g h
`
`i.m
`p.o.
`
`103
`ND
`
`68.5
`ND
`
`Cmax
`Brain
`ng/
`equiv
`
`4763
`1051
`1456
`
`
`Cmax
`Plas
`ma
`ng/g
`
`1306
`839
`915
`
`
`*
`
`
`*
`*
`
`739
`
`
`129
`ND
`
`Cmax
`Brain
`ng/
`equivs
`
`3626
`760
`1564
`
`
`Cmax
`Plasm
`a ng/g
`
`761
`865
`313
`
`
`*
`
`
`*
`*
`
`349
`
`
`258
`ND
`
`AUC
`(0-8 hr)
`Ng/g
`h
`
`726
`908
`48
`Auc (0-
`24 hr)
`ng/g h
`18
`Auc
`(0-96
`hr)
`ng/g h
`26
`8
`
`1653
`1453
`243
`Auc (0-24
`hr) ng/g
`h
`67
`Auc (0-
`96 hr)
`ng/g h
`
`64
`ND
`
`Cmax
`Brain
`ng/
`equiv
`
`2141
`1756
`8518
`
`
`574
`833
`134
`
`
`*
`
`
`*
`*
`
`357
`
`
`258
`ND
`
`The only clinically relevant pharmacokinetic interaction detected is confined to inhibitors of CYP3A
`resulting in enhanced bioavailability of buprenorphine. Based on these studies inhibitors of CYP 3A
`enzyme can potentially increase the hepatic toxicity of buprenorphine. Patients concomitantly
`administered inhibitors of CYP 3A should be closely monitored for markers of liver toxicity.
`This is reflected in the clinical pharmacokinetics and is taken into account in the SPC.
`
`Toxicology
`
` Single dose toxicity
`Extensive acute toxicity studies employing different routes of administration (i.v., s.c. i.m. and oral)
`are presented in which the toxicity of buprenorphine and naloxone are compared with the toxicity of
`mixtures of these components. These studies demonstrate that there is no synergistic enhancement of
`toxicity when buprenorphine and naloxone are co-administered.
`
` •
`
` Repeat dose toxicity (with toxicokinetics)
`Dietary toxicity studies of 28 days and 13 weeks duration in rats were conducted using buprenorphine:
`naloxone at a ratio of 4:1 in terms of the bases (i.e. the ratio intended for human use).
`The dietary route was selected for repeated dose toxicity evaluation of Suboxone since this route was
`relevant to the proposed sublingual route of human exposure. In addition to data on the dietary
`toxicity of Suboxone in rats, data on the toxicity of development formulations containing ratios of
`buprenorphine and naloxone of 1:1 and 3:2 for periods of up to 28 days in both the rat and the dog by
`a variety of enteral and parenteral routes of administration are presented.
`
`Clinical observations were aggressive behaviour and excessive grooming. An analgesic effect
`(prolonged time to tail flick) has been observed in females of the 2000 ppm group. Bodyweight was
`significant lower throughout the study for males only. Food consumption and food utilisation was
`decreased in males also. A treatment-related increase in adrenal weight adjusted for body weight was
`recorded for males receiving Suboxone. The adrenals were histologically normal and this apparent
`weight change was not considered to be of toxicological importance. No other organ weight changes
`were apparent that were considered to be related to treatment and no treatment-related abnormalities
`were observed at autopsy. Histological examination revealed an increased incidence and severity of
`mononuclear cell infiltration of the Harderian gland in females of all groups receiving Suboxone and
`in males receiving ≥500 ppm. However, as there is no known clinical effect of insult to the Harderian
`gland, the toxicological importance of these findings remains unclear. No toxicological relevant target
`
`
`
`©EMEA 2006
`
`8/42
`
`
`
`TEVA EXHIBIT 1011
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`organ toxicity was apparent apart from weight changes of the liver and histological effects on the
`kidneys, probably adaptive effects due to the high doses administered.
`
`Safety margins based on AUC were calculated based on human data from Clinical Study CR97/007:
`
`Rat : human buprenorphine ratios based on AUC (ng·h/ml)
`Table 7
`Dietary concentration
`Buprenorphine dose (mg)
`of Suboxone (ppm)
`
`4
`7.3
`28.2
`73.6
`93.9
`
`8
`4.4
`17.1
`44.7
`57.0
`
`16
`2.5
`9.7
`25.4
`32.4
`
`24
`2.0
`7.6
`20.0
`25.5
`
`6
`NC
`4.4
`68.0
`71.7
`
`100
`500
`1500
`2000
`
`100
`500
`1500
`2000
`
`
`Rat : human naloxone ratios based on AUC (ng·h/ml)
` Table 8
`Naloxone dose (mg)
`Dietary concentration
`of Suboxone (ppm)
`
`1
`NC
`15.1
`231.8
`244.5
`
`2
`NC
`8.5
`130.8
`137.9
`
`4
`NC
`5.0
`76.1
`80.3
`
`NC = Not calculated. Plasma concentration less than LLOQ (0.5 ng/ml).
`
`The toxicokinetic data obtained in rats following dietary administration of buprenorphine: naloxone at
`a ratio of 4:1 also suggests that both rats and dogs receiving development formulations of
`buprenorphine: naloxone at a ratio of 1:1 by the oral route would have received toxicologically
`significant exposures to both of the active ingredients.
`
`No novel toxicological aspects rose from the studies with a mixture of buprenorphine/naloxone in
`comparison with knowledge about the compounds alone. Based on toxicokinetic data raised from the
`dietary study with Suboxone, an exposure of animals sufficiently above the maximum therapeutic
`dose in humans has been reached. Clinical signs reflected the pharmacodynamics of the active
`ingredients.
`
` •
`
` Genotoxicity
`Standard in vitro and in vivo genotoxicity tests with buprenorphine and naloxone were negative
`indicating that both compounds are devoid of genotoxic properties.
`
` A
`
` 7-day dietary palatability study in rats, a subacute 28 day dietary toxicity study in rats and
`associated mutagenicity studies have also been completed in order to investigate the potential toxicity
`and genotoxicity of synthesis impurities and degradants of Suboxone.
`
`Synthesis impurity D (7,8-didehydronaloxone) present in naloxone was found clastogenic in vitro
`studies with human lymphocytes. The proposed specification limit of 7,8-didehydronaloxone will
`result in exposure below the Threshold of Toxicological Concern (TTC) of 1.5 µg/day which is
`recommended for setting acceptable daily intake limits of genotoxic impurities by the EU Draft
`Guideline on the Limits of Genotoxic Impurities (CHMP/SWP/5199/02).
`
` A
`
` series of other synthesis impurities and degradants was reviewed for structure-activity relationship
`and were reported to be devoid of structural alerts. However, the process used to determine alerting
`structures was not fully clear and needed further clarification. The applicant further provided sufficient
`information about the approaches used (in house and at FDA) in assessing structural alerts as part of
`
`
`
`©EMEA 2006
`
`9/42
`
`
`
`TEVA EXHIBIT 1011
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`the toxicological qualification of impurities and degradants. The applied approach for qualifying the
`impurities/degradants is acceptable.
`
` Carcinogenicity
`A 2-year dietary carcinogenicity study with Suboxone was conducted in rats at doses of 7, 30 and
`120 mg/kg/day, with estimated exposure multiples of 3 to 75 times, based on a human daily sublingual
`dose of 16 mg calculated on a mg/m² basis. Statistically significant increases in the incidence of
`benign testicular interstitial (Leydig's) cell adenomas were observed in all dosage groups.
`
` •
`
` A
`
` dose-related reduction in the