DATA SHEET
`
`SUBOXONE (buprenorphine + naloxone)
`2mg/0.5mg and 8mg/2mg Sublingual Tablets
`
`NAME OF THE DRUG
`SUBOXONE sublingual tablets contain buprenorphine hydrochloride and naloxone hydrochloride
`at a ratio of 4:1 buprenorphine : naloxone.
`
`DESCRIPTION
`SUBOXONE is an uncoated tablet intended for sublingual administration. It is available in two
`dosage strengths, 2mg buprenorphine + 0.5mg naloxone and 8mg buprenorphine + 2mg naloxone.
`Each tablet also contains lactose, mannitol, maize-starch, povidone, citric acid anhydrous, sodium
`citrate, magnesium stearate, acesulfame potassium and Lemon & Lime flavour
`
`Buprenorphine hydrochloride is a white powder, weakly acidic with limited solubility in water (19.5
`mg /mL at 37, pH 4.1). Chemically, it is 21-Cyclopropyl-7-(S) -1- hydroxy-1,2,2 -
`trimethylpropyl-6,14-endo –ethano-6,7,8,14-tetrahydrooripavine hydrochloride.. Buprenorphine
`hydrochloride has the molecular formula C29 H41 NO4 HCl and the molecular weight is 504.09. The
`CAS number is 53152-21-9.
`
`Naloxone hydrochloride is a white to slightly off-white powder that exists as the dihydrate and is
`soluble in water, in dilute acids and in strong alkali. Chemically, it is (-)-17-Allyl-4,5-epoxy-3, 14-
`dihydroxymorphinan-6-one hydrochloride dihydrate. Naloxone hydrochloride has the molecular
`formula C19 H21 NO4 HCl .2H2 O and the molecular weight is 399.87. The CAS number of naloxone
`hydrochloride dihydrate is 51481-60-8.
`
`The chemical structures of buprenorphine hydrochloride and naloxone hydrochloride dihydrate
`are:
`HO
`
`naloxone hydrochloride dihydrate
`
`
`PHARMACOLOGY
`Pharmacodynamic properties
`Buprenorphine is a µ (mu) opioid receptor partial agonist,  (kappa) opioid receptor antagonist. Its
`activity in opioid maintenance treatment is attributed to its slow dissociation from the µ receptors in
`the brain which reduces craving for opioids and opiate withdrawal symptoms. This minimises the
`need of the addicted patient for illicit opiate drugs.
`
`During clinical pharmacology studies in opiate-dependent subjects, buprenorphine demonstrated a
`ceiling effect on a number of parameters, including positive mood, “good effect”, and respiratory
`depression.
`
`Naloxone is an antagonist at µ (mu) opioid receptors. Because of its almost complete first pass
`metabolism, naloxone administered orally or sublingually has no detectable pharmacological
`activity. However, when administered intravenously to opiate dependent persons, the presence of
`
`
`
`- 1 -
`
`HO
`
`O
`
`O
`
`N
`OH
`
`.HCl. 2H20
`
`
`
`N
`
`O
`
`CH3O
`
`HO
`
`CH3
`C(CH3)3
`.HCl
`buprenorphine hydrochloride
`
`Page 1
`
`RB Ex. 2007
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`

`
`Suboxone Data Sheet, 21 March 2006
`
`
`
`naloxone in SUBOXONE produces marked opiate antagonist effects and opiate withdrawal,
`thereby deterring intravenous abuse.
`
`Pharmacokinetic properties:
`
`Absorption
`When taken orally, buprenorphine undergoes first-pass metabolism with N-dealkylation and
`glucuroconjugation in the small intestine and the liver. The use of SUBOXONE by the oral route is
`therefore inappropriate. SUBOXONE tablets are for sublingual administration.
`
`Plasma levels of buprenorphine and naloxone increased with the sublingual dose of SUBOXONE
`although the increases were not directly dose-proportional (Table 1). The levels of naloxone were
`too low to determine area under the curve values. There was a wide inter-patient variability in the
`sublingual absorption of buprenorphine and naloxone from SUBOXONE tablets, but within subjects
`the variability was low. Naloxone did not appear to affect the pharmacokinetics of buprenorphine.
`SUBOXONE tablets are expected to deliver similar plasma concentrations of buprenorphine as
`tablets containing buprenorphine alone, with sublingual dosing.
`
`
`
`Table 1.
`
`
`
`Mean Cmax and AUC of buprenorphine and naloxone following single
`sublingual doses of SUBOXONE tablets.
`8 mg SUBOXONE
`16 mg SUBOXONE
`(8 mg buprenorphine
`(16 mg buprenorphine
`+ 2 mg naloxone)
`+ 4 mg naloxone)
`
`4 mg SUBOXONE
`(4 mg buprenorphine
`+ 1 mg naloxone)
`
`24 mg SUBOXONE
`(24 mg buprenorphine
`+ 6 mg naloxone)
`
`
`22
`2.16
`(0.68-4.33)
`12.88
`(5.18-23.24)
`
`20
`0.12
`(0.06-0.25)
`
`22
`3.33
`(1.10-6.36)
`22.14
`(8.62-44.11)
`
`21
`0.23
`(0.09-0.42)
`
`21
`5.87
`(2.48-10.0)
`37.67
`(18.71-74.13)
`
`20
`0.39
`(0.07-1.15)
`
`12
`6.44
`(3.43-10.5)
`47.55
`(24.23-96.43)
`
`12
`0.47
`(0.08-1.02)
`
`Buprenorphine
`Subjects
`Cmax
`ng/mL
`AUC0-tn
`h. ng/mL
`Naloxone
`Subjects
`Cmax
`ng/mL
`
`
`
`Naloxone did not affect the pharmacokinetics of buprenorphine and both SUBOXONE and
`buprenorphine deliver similar plasma concentrations of buprenorphine. Compared with intravenous
`administration, the mean absolute bioavailability of buprenorphine from sublingual SUBOXONE
`8mg tablets was 13.6% (range 5.1-24.9%) and that of naloxone was approximately 3%.
`
`Distribution
`The absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2
`to 5 hours). Following intravenous administration, naloxone is rapidly distributed (distribution half-
`life of around 4 minutes).
`
`Buprenorphine is highly lipophilic which leads to rapid penetration of the blood-brain barrier. The
`drug is around 96% protein bound primarily to alpha and beta globulin. Naloxone is approximately
`45% protein bound, primarily to alpha and beta globulin.
`
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`Metabolism and elimination
`In animals and man buprenorphine is metabolised by Phase 1 (oxidative) and Phase 2
`(conjugation) reactions. It is oxidatively metabolised by N-dealkylation to norbuprenorphine by
`CYP 3A4. In in vitro metabolic studies addition of specific inhibitors of CYP 3A4 (e.g.
`ketoconazole, gestodene, nifedipine, norfluoxetine, ritonavir) inhibited formation of
`norbuprenorphine. (see also PRECAUTIONS and Interactions with Other Drugs)There was no
`indication of the involvement of CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 in the N-
`dealkylation of buprenorphine. Buprenorphine was a weak competitive inhibitor of CYP 2D6 and
`CYP 3A4. Norbuprenorphine is a µ (mu) agonist with weak intrinsic activity and is considered to be
`an inactive metabolite.
`
`Naloxone undergoes direct glucuroconjugation to naloxone-3-glucuronide as well as N-dealkylation
`and reduction of the 6-oxo group.
`
`Elimination of buprenorphine is bi- or tri-exponential, with a long terminal elimination phase (mean
`half-life of 34.6 hours, range 20.4-72.9 hours), due in part to re-absorption of buprenorphine after
`intestinal hydrolysis of the conjugated metabolite, and in part to the highly lipophilic nature of the
`molecule. Naloxone has a short elimination half-life (mean 1.1 hours, range 0.63-1.94 hours).
`
`Buprenorphine is essentially eliminated in the faeces by biliary excretion of the glucuroconjugated
`metabolites (70%), the rest being eliminated in the urine. Naloxone is excreted in the urine.
`
`Elderly: No pharmacokinetic data in elderly patients are available
`
`CLINICAL TRIALS
`All trials used buprenorphine in conjunction with psychosocial counselling 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.
`
`Efficacy and safety data for SUBOXONE are primarily derived from a one-year clinical trial,
`comprising a 4 week randomised double blind comparison of SUBOXONE, buprenorphine and
`placebo tablets followed by a 48 week safety study of SUBOXONE (Study CR96/013 +
`CR96/014).
`
`In the double blind placebo- and active controlled study, 326 heroin-addicted subjects were
`randomly assigned to either SUBOXONE 16 mg per day, 16 mg buprenorphine per day or placebo
`tablets. For subjects randomised to either active treatment, dosing began with one 8 mg tablet of
`buprenorphine on Day 1, followed by 16 mg (two 8 mg tablets) of buprenorphine on Day 2. On Day
`3, those randomised to receive SUBOXONE were switched to the combination tablet. Subjects
`were seen daily in the clinic (Monday through Friday) for dosing and efficacy assessments. Take-
`home doses were provided for weekends. The primary study comparison was to assess the
`efficacy of buprenorphine and SUBOXONE individually against placebo. The percentage of thrice-
`weekly urine samples that were negative for non-study opioids was statistically higher for both
`SUBOXONE versus placebo (p < 0.0001) and buprenorphine versus placebo (p < 0.0001).
`
`
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`Suboxone Data Sheet, 21 March 2006
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`INDICATIONS
`Treatment of opiate dependence, within a framework of medical, social and psychological
`treatment. Naloxone is included in SUBOXONE to deter intravenous misuse of the product.
`
`CONTRAINDICATIONS
`Hypersensitivity to buprenorphine or naloxone or any other component of the tablet.
`Children less than 16 years of age.
`Severe respiratory or hepatic insufficiency. (Child-Pugh B or C)
`Acute intoxication with alcohol or other CNS depressant.
`Pregnant Women
`Breast-feeding.
`
`PRECAUTIONS
`General: SUBOXONE should be administered with caution in elderly or debilitated patients and
`those with impairment of hepatic, pulmonary, or renal function; myxoedema or hypothyroidism,
`adrenal cortical insufficiency (eg Addison's disease); CNS depression or coma; toxic psychoses;
`prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.
`
`Buprenorphine increases intracholedochal pressure as do other opiates. Therefore, caution should
`be exercised when SUBOXONE is to be administered to patients with dysfunction of the biliary
`tract.
`
`As with other opioids, caution is advised in patients using buprenorphine and having:
`- Hypotension,
`- Prostatic hypertrophy and urethral stenosis.
`
`As with other mu-opiate receptor agonists, the administration of SUBOXONE may obscure the
`diagnosis or clinical course of patients with acute abdominal conditions.
`
`Respiratory Depression: SUBOXONE is intended for sublingual use only. Significant respiratory
`depression has been associated with buprenorphine, particularly by the intravenous route. A
`number of deaths have occurred when addicts have intravenously misused tablets containing
`buprenorphine as the only active, 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 CNS depressants at the same time as receiving
`SUBOXONE.
`
`In the event of depression of respiratory or cardiac function, primary attention should be given to
`the re-establishment of adequate respiratory exchange through provision of a patent airway and
`institution of assisted or controlled ventilation. Oxygen, intravenous fluids, vasopressors, and other
`supportive measures should be employed as indicated. High doses of naloxone hydrochloride 10-
`35 mg/70 kg may be of limited value in the management of buprenorphine overdose.
`
`SUBOXONE 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-existing respiratory depression)
`
`CNS Depression: Patients receiving SUBOXONE in the presence of other narcotic analgesics,
`general anaesthetics, benzodiazepines, phenothiazines, other tranquillisers, 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. SUBOXONE should be used cautiously with MAOIs, based on experience with
`morphine.
`
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`Hepatitis, Hepatic Events: Hepatic necrosis and hepatitis with jaundice have been reported with
`buprenorphine use. 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. Serious cases of acute hepatic injury have also been
`reported in a context of misuse, especially by the intravenous route. These hepatic injuries were
`dose-related, and could be due to mitochondrial toxicity. Pre-existing or acquired mitochondrial
`impairment (genetic diseases, viral infections particularly chronic hepatitis C, alcohol abuse,
`anorexia, associated mitochondrial toxins, e.g. aspirin, isoniazid, valproate, amiodarone, antiviral
`nucleoside analogues) could promote the occurrence of such hepatic injuries. These co-factors
`must be taken into account before prescribing SUBOXONE and during treatment monitoring.
`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
`biological and etiological evaluation is recommended when a hepatic event is suspected.
`Depending upon the findings, the medicinal product may be discontinued cautiously so as to
`prevent withdrawal syndrome and to prevent a return to drug addiction. If the drug treatment is
`continued, hepatic function should be monitored closely.
`
`Hepatic Disease: Because buprenorphine is metabolised by the liver, its activity may be increased
`and/or extended in those individuals with impaired hepatic function. Naloxone metabolism may
`also be impaired in hepatic failure patients. Because hepatic elimination plays a relatively large
`role (~70%) in the overall clearance of SUBOXONE, lower initial doses and cautious titration of
`dosage may be required in patients with hepatic dysfunction.
`
`CYP3A4 Inhibitors: Because CYP3A4 inhibitors may increase concentrations of buprenorphine,
`patients already treated with CYP3A4 inhibitors should have their dose of SUBOXONE titrated
`carefully since a reduced dose may be required in these patients (see Interactions with Other
`Drugs).
`
`Renal Disease: Renal elimination plays a relatively small role (~30%) in the overall clearance of
`buprenorphine. Therefore no dose modification based on renal function is required. Metabolites of
`buprenorphine accumulate in patients with renal failure. Caution is recommended when dosing
`patients with severe renal impairment (CLcr <30 ml/min).
`
`Use in Ambulatory Patients: SUBOXONE may impair the mental or physical abilities required for
`the performance of potentially dangerous tasks such as driving a car or operating machinery.
`Patients should be cautioned accordingly. Like other opiates, SUBOXONE may produce
`orthostatic hypotension in ambulatory patients.
`
`Head Injury and Increased Intracranial Pressure: SUBOXONE, like other potent opiates may
`itself 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 can produce miosis and changes in the level of consciousness that may
`interfere with patient evaluation.
`
`Opiate Withdrawal Effects: Because SUBOXONE contains naloxone, it is highly likely to
`produce marked and intense opiate withdrawal symptoms if injected.
`
`SUBOXONE may produce withdrawal symptoms in opiate dependent subjects if it is administered
`too soon after another opiate. Discontinuation of treatment may result in a withdrawal syndrome
`that may be delayed. Studies in animals, as well as clinical experience, have showed that
`buprenorphine may produce dependence but at a lower level than morphine. Consequently, it is
`important to follow the DOSAGE AND ADMINISTRATION recommendations.
`
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`Neonatal Abstinence Syndrome: Neonatal withdrawal has been reported in the infants of women
`treated with buprenorphine during pregnancy. Time to onset of withdrawal symptoms ranged from
`Day 1 to Day 8 of life with most (69%) occurring on Day 1. Adverse events associated with
`neonatal withdrawal syndrome included hypertonia, neonatal tremor, neonatal agitation, and
`myoclonus. There have been rare reports of convulsions and in one case, apnoea and
`bradycardia were also reported. In many cases the withdrawal was serious and required treatment
`(See Use in Pregnancy).
`
`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 oedema,
`and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine or
`naloxone is a contraindication to SUBOXONE use.
`
`Carcinogenicity & Mutagenicity
`Carcinogenicity:
`In mice, no evidence for carcinogenicity due to buprenorphine was noted in life-time studies at
`dietary doses of up to 100mg/kg/day, which equates to ca 14-fold human exposure at the
`maximum recommended clinical dose of 32mg based on body surface area.
`
`In rats, statistically significant (trend test adjusted for survival) dose-related increases in testicular
`interstitial (Leydig) cell tumours occurred at a dietary buprenorphine dose of 55mg/Kg/day (16 fold
`the maximal recommended human sublingual dose of 32mg, on a mg/m2 basis); the no-effect dose
`was 5.4mg/Kg/day (twice the maximal human dose, on a mg/m2 basis).
`
`The carcinogenic potential of naloxone alone has not been investigated in long term animal
`studies.
`
`In a 2 year dietary study with Suboxone in rats, Leydig cell adenomas were found at doses of 6-
`115mg/kg/day, associated with respective exposures (plasma AUC) to buprenorphine and
`naloxone of 2-21 fold, and up to 58 fold, anticipated human exposure. A NOEL was not
`established in the study.”
`
`Mutagenicity: In genotoxic studies using buprenorphine and naloxone (9:2), assays for bacterial
`gene mutations and chromosomal damage (human lymphocytes in vitro and rat micronucleus test
`in vivo) were negative.
`
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`Impairment of Fertility
` There were no effects on mating performance or fertility in rats following buprenorphine treatment
`at oral doses ca 20 times the maximum clinical dose of 32mg/day (based on mg/m2). Dietary
`administration of Suboxone to rats at doses of 47mg/kg/day or greater (estimated respective
`buprenorphine and naloxone exposures 14 and 24 times the anticipated clinical exposure, based
`on plasma AUC) resulted in reduced female conception rates. A dietary dose of 9.4mg/kg/day
`(twice the anticipated clinical exposure for both buprenorphine (based on AUC) and naloxone
`(based on mg/m2) had no adverse effect on fertility.
`
`Use In Pregnancy (Category C)
`In rats, oral administration of buprenorphine at doses up to 20 times the maximum clinical dose of
`32mg/day (based on mg/m2) prior to and during gestation and lactation resulted in reduced
`implantation, fewer live births, and reduced pup weight gain and survival. There was no evidence
`of teratogenicity in rats and rabbits following parenteral administration of buprenorphine during the
`period of organogenesis, although there was embryofoetal toxicity, and reduced pup viability and
`developmental delays in rats. There was no evidence of teratogenicity in rats and rabbits following
`oral or intramuscular administration of maternally toxic doses of combinations of burprenorphine +
`naloxone during the period of organogenesis, although post-implantation losses were increased.
`In rats, oral (20 times maximum clinical dose, based on mg/m2) or intramuscular administration of
`buprenorphine from late gestation to weaning was associated with increased stillbirths, reduced
`postnatal survival, and delayed postnatal development including weight gain and some
`neurological functions (surface righting reflex and startle response).
`
`There are no adequate or well controlled studies of SUBOXONE in pregnant women.
`Buprenorphine readily crosses the placental barrier, and may cause respiratory depression in
`neonates. During the last three months of pregnancy, chronic use of buprenorphine may be
`responsible for a withdrawal syndrome in neonates. SUBOXONE is contraindicated in pregnancy
`(see CONTRAINDICATIONS). Continued use of heroin during pregnancy is associated with
`significant risk to the mother and the foetus and neonate.
`
`
`
`
`
`Use In Lactation
`Animal studies indicate buprenorphine has the potential to inhibit lactation or milk production.
`In rats, oral (20 times maximum clinical dose, based on mg/m2) or intramuscular administration of
`buprenorphine from late gestation to weaning was associated with increased stillbirths, reduced
`postnatal survival, and delayed postnatal development including weight gain and some
`neurological functions (surface righting reflex and startle response). The no effect level for
`developmental effects was twice the maximum clinical dose, based on mg/m2. Because
`buprenorphine is excreted into human milk, SUBOXONE should not be used in breast-feeding
`women.
`
`Use in children:
`SUBOXONE is not recommended for use in children. The safety and effectiveness of SUBOXONE
`in subjects below the age of 16 has not been established.
`
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`Suboxone Data Sheet, 21 March 2006
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`Interactions with Other Drugs
`A number of deaths and cases of coma have occurred when addicts have intravenously misused
`buprenorphine and benzodiazepines concomitantly. Patients should be warned of the potential
`danger of the intravenous self-administration of benzodiazepines or other CNS depressants at the
`same time as receiving SUBOXONE (see PRECAUTIONS).
`
`CYP3A4 inhibitors: An interaction study of buprenorphine with ketoconazole (a potent inhibitor of
`CYP3A4) resulted in increased Cmax and AUC of buprenorphine (approximately 50% and 70%
`respectively) and, to a lesser extent, of norbuprenorphine. Patients receiving SUBOXONE should
`be closely monitored, and may require dose-reduction if combined with potent CYP3A4 inhibitors
`e.g. protease inhibitors like ritonavir, nelfinavir or indinavir, azole antifungals like ketoconazole or
`itraconazole, calcium channel antagonists, and macrolide antibiotics (see PRECAUTIONS).
`
`CYP3A4 inducers: The interaction of buprenorphine with CYP3A4 inducers has not been
`investigated; therefore it is recommended that patients receiving SUBOXONE should be closely
`monitored if inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-
`administered.
`
`Effects on Laboratory Tests
`Athletes should be aware that this medicine may cause a positive reaction to “anti-doping” tests.
`
`ADVERSE REACTIONS
`Adverse events reported to occur by at least 1% of patients being treated in clinical trials of
`SUBOXONE (CR96/013 + CR96/014) are shown in Table 2.
`
`
`
`Very Common Adverse Events reported by at least 10% 0f subjects
`Headache, withdrawal syndrome
`Constipation, nausea
`Insomnia
`Sweating
`Common Adverse Events reported by at least 1% of subjects
`Asthenia, chills, fever, flu syndrome, infection, malaise, abdominal pain, back
`pain, chest pain, pain, accidental injury
`Migraine, hypertension, vasodilation.
`Anorexia, diarrhoea, nausea/vomiting, vomiting, dyspepsia, liver function
`abnormal, flatulence.
`Peripheral oedema, weight decreased
`
`Table 2
`Body as a whole
`Digestive System
`Nervous System
`Skin and Appendages
`
`Body as a whole
`
`Cardiovascular System
`Digestive System
`
`Metabolic/Nutritional
`Disorders
`Musculoskeletal System
`Nervous System
`
`Respiratory System
`Skin and Appendages
`Special Senses
`Urogenital System
`
`The most common adverse events reported were those related to withdrawal symptoms (e.g.
`abdominal pain, diarrhoea, muscle aches, anxiety, sweating). In patients with marked drug
`dependence, initial administration of buprenorphine can produce a withdrawal effect similar to that
`associated with naloxone.
`
`As with other opiates, orthostatic hypotension can occur (see PRECAUTIONS).
`
`
`Arthralgia, leg cramps, myalgia.
`Anxiety, depression, dizziness, hypertonia, nervousness, paresthesia,
`somnolence, thinking abnormal, libido decreased.
`Cough increased, pharyngitis, rhinitis.
`Rash, pruritus, urticaria
`Lacrimation disorder, amblyopia
`Impotence, urine abnormality
`
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`Suboxone Data Sheet, 21 March 2006
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`Post-marketing experience with buprenorphine alone
`Post-marketing experience with buprenorphine alone for treatment of opiate dependency has been
`associated with the following rare side effects: respiratory depression and coma, hallucinations,
`neonatal withdrawal syndrome, neonatal tremor, neonatal feeding disorder, foetal disorders,
`convulsions, confusion, miosis, weight decrease, asphyxia, hypoventilation, pruritus, angioedema,
`heart rate and rhythm disorders, and deaths.
`
`
`
`
`
`Additionally, post-marketing experience with SUBOXONE for treatment of opiate dependency has
`been associated rarely with the following side effects: insomnia, reduced feeling, anorexia (see
`also Table 2 above), amnesia, convulsions, blood in vomit, fatigue, jaundice, swollen joints,
`miscarriage, shortness of breath, and suicide ideation.
`
`Cases of hepatitis with jaundice, hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic
`encephalopathy, and asymptomatic elevations in hepatic transaminases have been reported with
`buprenorphine use (see PRECAUTIONS).
`
`In cases of intravenous misuse of buprenorphine, local reactions, sometimes septic, and potentially
`serious acute hepatitis have been reported.
`
`Cases of acute or chronic hypersensitivity to buprenorphine have been reported with symptoms
`including rashes, hives, pruritus and reported cases of bronchospasm, angioneurotic oedema, and
`anaphylactic shock. (see PRECAUTIONS and CONTRAINDICATIONS).
`
`DOSAGE AND ADMINISTRATION
`Treatment with SUBOXONE sublingual tablets is intended for adults and children aged 16 years or
`over who have agreed to be treated for addiction. When initiating SUBOXONE treatment, the
`physician should be aware that it can precipitate withdrawal in opioid-dependent patients if given
`too soon after the administration of heroin, methadone or another opiate.
`
`The route of administration of SUBOXONE is sublingual. SUBOXONE tablets should not be
`swallowed as this reduces the bioavailability of the medicine. Physicians must advise patients that
`the sublingual route is the only effective and safe route of administration for this drug.
`
`Please note: The following instructions refer to the buprenorphine content of each dose.
`SUBOXONE 8mg/2mg (buprenorphine/naloxone) is referred to as the 8mg dose and SUBOXONE
`2mg/0.5mg (buprenorphine/naloxone) is referred to as the 2mg dose.
`
`Method of Administration
`Suboxone tablets are to be placed under the tongue until dissolved, which usually requires 2 to 10
`minutes. The dose is made up from 2 mg and 8 mg sublingual tablets, which may be taken all at the
`same time or in two divided portions; the second portion to be taken directly after the first portion has
`dissolved.
`
`Starting SUBOXONE
`An adequate maintenance dose, titrated to clinical effectiveness, should be achieved as rapidly as
`possible to prevent undue opiate withdrawal symptoms due to inadequate dosage.
`
`Prior to induction, consideration should be given to the type of opiate dependence (i.e., long- or
`short-acting opiate), the time since last opiate use and the degree or level of opiate dependence.
`
`Patients taking Street Heroin (or Other Short-acting Opiates): When treatment starts the dose
`of SUBOXONE should be taken at least 6 hours after the patient last used opiates or when the
`early signs of withdrawal appear. The recommended starting dose is 4 mg SUBOXONE on Day One,
`with a possible additional 4 mg depending on the individual patient’s requirement.
`
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`Suboxone Data Sheet, 21 March 2006
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`Patients on Methadone: Before starting treatment with SUBOXONE, the maintenance dose of
`methadone should be reduced to a maximum of 30mg per day. The first dose of SUBOXONE
`should be taken at least 24 hours after the patient last used methadone. The initial 4mg
`SUBOXONE induction dose should ideally be administered when early signs of withdrawal are
`evident.
`
`Dosage Adjustment and Maintenance
`The dose of SUBOXONE should be increased progressively according to the clinical effect in the
`individual patient and should not exceed a maximum daily dose of 32 mg. The dosage is adjusted
`according to reassessments of the clinical and psychological status of the patient.
`
`Less than Daily Dosing of SUBOXONE
`After a satisfactory period of stabilisation has been achieved the frequency of dosing may be
`decreased to dosing every other day at twice the individually titrated daily dose. For example, a
`patient stabilised to receive a daily dose of 8mg may be given 16mg on alternate days, with no
`medication on the intervening days. However, the dose given on any one day should not exceed
`32mg.
`
`In some patients, after a satisfactory period of stabilisation has been achieved, the frequency of
`dosing may be decreased to 3 times a week (for example on Monday, Wednesday and Friday).
`The dose on Monday and Wednesday should be twice the individually titrated daily dose, and the
`dose on Friday should be three times the individually titrated daily dose, with no medication on the
`intervening days. However, the dose given on any one day should not exceed 32mg.
`
`Reducing Dosage and Stopping Treatment
`The decision to discontinue therapy with SUBOXONE should be made as part of a comprehensive
`treatment plan. A gradual dose taper over a period of 21 days is shown in Table 3.
`
`
`
`Table 3.
`Week
`
`20mg
`Maintenance dose
`16mg
`8mg
`4mg
`
`Gradual dose taper schedule
`16mg
`Maintenance dose
`12mg
`8mg
`4mg
`
`8mg
`Maintenance dose
`8mg
`4mg
`4mg
`
`1
`2
`3
`
`
`
`OVERDOSAGE
`Manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory
`depression and death.
`
`In the event of accidental overdose, general supportive measures should be instituted including
`close monitoring of respiratory and cardiac status of the patient. The major symptom requiring
`intervention is respiratory depression, which could lead to respiratory arrest and death. If the
`patient vomits, care must be taken to prevent aspiration of the vomitus.
`
`Treatment
`In the event of depression of respiratory or cardiac function, primary attention should be given to
`the re-establishment of adequate respiratory exchange through provision of a patent airway and
`institution of assisted or controlled ventilation. Oxygen, intravenous fluids, vasopressors, and other
`supportive measures should be employed as indicated. High doses of naloxone hydrochloride 10-
`35 mg/70 kg may be of limited value in the management of buprenorphine overdose.
`
`The long duration of action of SUBOXONE should be taken into consideration when determining
`the length of treatment needed to reverse the effects of an overdose.
`
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`Suboxone Data Sheet, 21 March 2006
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`PRESENTATION
`SUBOXONE is supplied as white, hexagonal sublingual tablets containing 2mg buprenorphine +
`0.5mg naloxone and 8mg buprenorphine + 2mg naloxone. The tablets are packed in aluminium /
`aluminium blister strips of 7 tablets in pack sizes of 28 tablets.
`
`Store below 30oC.
`
`CLASSIFICATION
`Controlled Drug: C4
`
`NAME AND ADDRESS OF SPONSOR
`Reckitt Benckiser
`289 Lincoln Road
`Henderson
`Auckland
`
` DATE OF PREPARATION: 21 March 2006
`
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