Download ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
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1.
NAME OF THE MEDICINAL PRODUCT
Suboxone 2 mg/0.5 mg sublingual tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2 mg buprenorphine (as buprenorphine hydrochloride) and 0.5 mg naloxone (as
naloxone hydrochloride dihydrate).
Excipients:
lactose 42 mg
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Sublingual tablet
White hexagonal biconvex tablets, embossed with a sword logo on one side and “N2” on the reverse
side.
4.
CLINICAL PARTICULARS
4.1
Therapeutic indications
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.
Treatment is intended for use in adults and adolescents over 15 years of age who have agreed to be
treated for addiction.
4.2
Posology and method of administration
Treatment must be under the supervision of a physician experienced in the management of
opiate dependence/addiction.
Each Suboxone sublingual tablet contains buprenorphine and naloxone. Suboxone containing 2 mg
buprenorphine and 0.5 mg naloxone is referred to as the "2 mg" tablets.
Physicians must warn patients that the sublingual route is the only effective and safe route of
administration for this medicinal product (see section 4.4). Suboxone sublingual tablets are to be
placed under the tongue until dissolved, which usually requires 5 to 10 minutes. The dose is made up
from Suboxone 2 mg/0.5 mg and Suboxone 8 mg/2 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.
Adults:
Baseline liver function tests and documentation of viral hepatitis status is recommended prior to
commencing therapy. Patients who are positive for viral hepatitis, on concomitant medicinal products
(see section 4.5) and/or have existing liver dysfunction are at risk of accelerated liver injury. Regular
monitoring of liver function is recommended (see section 4.4).
Induction:
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Prior to treatment induction, consideration should be given to the type of opioid dependence (i.e. long- or
short-acting opioid), the time since last opioid use and the degree of opioid dependence. To avoid
precipitating withdrawal, induction with Suboxone or buprenorphine only tablets should be undertaken
when objective and clear signs of withdrawal are evident.
Initiation therapy:
The recommended starting dose is one to two tablets of Suboxone 2 mg/0.5 mg sublingual tablets. An
additional one to two tablets of the Suboxone 2 mg/0.5 mg may be administered on day one depending on
the individual patient’s requirement.
Opioid-dependent drug addicts who have not undergone withdrawal: When treatment starts, the first
dose of Suboxone should be taken when signs of withdrawal appear, but not less than 6 hours after the
patient last used opioids (eg. heroin; short acting opioids).
Patients receiving methadone: Before beginning Suboxone therapy, the dose of methadone must be
reduced to a maximum of 30 mg/day. The first dose of Suboxone should be taken when signs of
withdrawal appear, but not less than 24 hours after the patient last used methadone. Buprenorphine
may precipitate symptoms of withdrawal in patients dependent upon methadone.
Dosage adjustment and maintenance: The dose of Suboxone should be increased progressively
according to the clinical effect of the individual patient and should not exceed a maximum single daily
dose of 24 mg. The dosage is titrated according to reassessment of the clinical and psychological
status of the patient and should be made in steps of 2-8 mg.
During the initiation of treatment, daily dispensing of buprenorphine is recommended. After
stabilisation, a reliable patient may be given a supply of Suboxone sufficient for several days of
treatment. It is recommended that the amount of Suboxone be limited to 7 days or according to local
requirements.
Less than daily dosing: After a satisfactory stabilisation has been achieved the frequency of Suboxone
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 8 mg may be given 16 mg on alternate days,
with no dose on the intervening days. However, the dose given on any one day should not exceed
24 mg. In some patients, after a satisfactory stabilisation has been achieved, the frequency of
Suboxone 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 dose on the
intervening days. However, the dose given on any one day should not exceed 24 mg. Patients
requiring a titrated daily dose > 8 mg/day may not find this regimen adequate.
Dosage reduction and termination of treatment: After a satisfactory stabilisation has been achieved, if
the patient agrees, the dosage may be reduced gradually to a lower maintenance dose; in some
favourable cases, treatment may be discontinued. The availability of the sublingual tablet in doses of
2 mg and 8 mg allows for a downward titration of dosage. For patients who may require a lower
buprenorphine dose, buprenorphine 0.4 mg sublingual tablets may be used. Patients should be
monitored following termination of treatment because of the potential for relapse.
Elderly:
No data is available on elderly patients.
Paediatrics:
Suboxone is not recommended for use in children below age 15 years due to lack of data on safety and
efficacy.
Patients with impaired hepatic function:
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The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown.
Since both active substances are extensively metabolized, the plasma levels will be expected to be
higher in patients with moderate and severe hepatic impairment. It is not known whether both active
substances are affected to the same extent.
As Suboxone pharmacokinetics may be altered in patients with hepatic insufficiency, lower initial
doses and careful dose titration in patients with mild to moderate hepatic impairment are
recommended (see section 5.2).
Patients with impaired renal function:
Modification of the Suboxone dose is not required in patients with renal insufficiency. Caution is
recommended when dosing patients with severe renal impairment (CLcr < 30 ml/min) (see section 5.2).
4.3
Contraindications
Suboxone is contraindicated in the following instances:
•
hypersensitivity to buprenorphine, to naloxone, or to any of the excipients,
•
severe respiratory insufficiency,
•
severe hepatic insufficiency,
•
acute alcoholism or delirium tremens.
4.4
Special warnings and precautions for use
Due to the lack of data in adolescents (age 15-<18), Suboxone should be used only with caution in this
age group.
Patients should be closely monitored during the switching period from buprenorphine or methadone to
Suboxone since withdrawal symptoms have been reported.
Diversion:
Diversion refers to the introduction of buprenorphine into the illicit market either by patients or by
individuals who obtain the medicinal product through theft from patients or pharmacies. This
diversion may lead to new addicts using buprenorphine as the primary drug of abuse, with the risks of
overdose, spread of blood borne viral infections, respiratory depression and hepatic injury. Because
the naloxone in the combination tablet precipitated withdrawal in individuals dependent on heroin,
methadone, or other full agonists, Suboxone is expected to be less likely to be diverted for intravenous
use.
Precipitated withdrawal:
When initiating treatment with buprenorphine, the physician must be aware of the partial agonist
profile of buprenorphine and that it can precipitate withdrawal in opioid-dependent patients
particularly if administered less than 6 hours after the last use of heroin or other short acting opioid, or
if administered less than 24 hours after the last dose of methadone (see section 4.2). Conversely,
withdrawal symptoms may also be associated with suboptimal dosing.
The risk of serious undesirable effects such as overdose or treatment dropout is greater if a patient is
under dosed with Suboxone and continues to self medicate withdrawal symptoms with opioids,
alcohol or other sedative-hypnotics in particular benzodiazepines.
Dependence:
Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration produces
dependence of the opioid type.
Discontinuation of treatment may result in a withdrawal syndrome that may be delayed.
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Suboxone may cause drowsiness, particularly when taken together with alcohol or central nervous
system depressants (such as tranquilisers, sedatives or hypnotics) (see section 4.5).
Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may produce
dependence but at a lower level than morphine.
Respiratory depression:
A number of cases of death due to respiratory depression have been reported, particularly when
buprenorphine was used in combination with benzodiazepines (see section 4.5), or when
buprenorphine was not used according to prescribing information.
Deaths have been reported in association with concomitant administration of buprenorphine and other
depressants such as alcohol or other opioids.
Hepatitis and hepatic events:
Cases of acute hepatic injury have been reported in opioid-dependent addicts both in clinical trials and
in post marketing 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 use of other
potentially hepatotoxic medicines, and ongoing injecting drug use may have a causative or
contributory role. These underlying factors must be taken into consideration before prescribing
Suboxone and during treatment. When a hepatic event is suspected, further biological and etiological
evaluation is required. Depending upon the findings, the medicinal product may be discontinued
cautiously so as to prevent withdrawal symptoms and to prevent a return to illicit drug use. If the
treatment is continued, hepatic function should be monitored closely.
As buprenorphine is an opioid, pain as a symptom of a disease may be attenuated.
Athletes must be aware that this medicine may cause a positive reaction to ‘anti-doping’ tests.
As with other opioids, caution is requested in patients using buprenorphine and having head injury,
increased intracranial pressure, hypotension, prostatic hypertrophy or urethral stenosis.
This product should be used with care in patients with: asthma or respiratory insufficiency (cases of
respiratory depression have been reported with buprenorphine); renal insufficiency (30 % of the
administered dose is eliminated by the renal route; thus, renal elimination may be prolonged); hepatic
insufficiency (hepatic metabolism of buprenorphine may be altered) (see section 4.3).
Medicines that inhibit the enzyme CYP3A4 may give rise to increased concentrations of
buprenorphine. A reduction of the Suboxone dose may be needed. Patients already treated with
CYP3A4 inhibitors should have their dose of Suboxone titrated carefully since a reduced dose may be
sufficient in these patients (see section 4.5).
The concomitant use of monoamine oxidase inhibitors (MAOI) might produce exaggeration of the
effects of opioids, based on experience with morphine.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.
4.5
Interaction with other medicinal products and other forms of interaction
Suboxone should not be taken together with:
•
alcoholic drinks or medications containing alcohol, as alcohol increases the sedative effect of
buprenorphine (see section 4.7).
Suboxone should be used cautiously when co-administered with:
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•
benzodiazepines: This combination may result in death due to respiratory depression of central
origin. Therefore, dosages must be limited and this combination must be avoided in cases where
there is a risk of misuse (see section 4.4).
•
other central nervous system depressants, other opioid derivatives (e.g. methadone, analgesics
and antitussives), certain antidepressants, sedative H1-receptor antagonists, barbiturates,
anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances: these
combinations increase central nervous system depression. The reduced level of alertness can
make driving and using machines hazardous.
•
CYP3A4 inhibitors: an interaction study of buprenorphine with ketoconazole (a potent inhibitor
of CYP3A4) resulted in increased Cmax and AUC (area under the curve) of buprenorphine
(approximately 70 % and 50 % 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 or azole antifungals such as ketoconazole or itraconazole).
•
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 coadministered.
To date, no notable interaction has been observed with cocaine, the agent most frequently used by
multi-drug abusers in association with opioids.
4.6
Pregnancy and lactation
Pregnancy: There is very limited experience with buprenorphine/naloxone in pregnant women. Studies
in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is
unknown.
Towards the end of pregnancy high doses of buprenorphine may induce respiratory depression in the
neonate even after a short period of administration. Long-term administration of buprenorphine during
the last three months of pregnancy may cause a withdrawal syndrome in the neonate.
Suboxone should not be used during pregnancy. If it is the prescriber’s opinion that therapy in
pregnancy is required, the use of buprenorphine may be considered according to the local
buprenorphine labeling.
In case pregnancy occurs while on Suboxone treatment, the mother and the unborn child should be
closely monitored and switched to buprenorphine if further treatment is required.
Breast-feeding: It is unknown whether naloxone is excreted in human breast milk. Buprenorphine and
its metabolites are excreted in human breast milk. In rats buprenorphine has been found to inhibit
lactation. Therefore, breast-feeding should be discontinued during treatment with Suboxone.
4.7
Effects on ability to drive and use machines
In general Suboxone has minor to moderate influence on the ability to move safely in traffic, use
machines, or perform other hazardous activities. Suboxone may cause drowsiness, dizziness, or
impaired thinking, particularly when taken together with alcohol or central nervous system
depressants. Therefore caution is advised when performing the above mentioned activities (see
sections 4.4 and 4.5).
4.8
Undesirable effects
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The most common-treatment related undesirable effects reported during clinical trials with Suboxone
were those related to withdrawal symptoms (e.g. abdominal pain, diarrhoea, muscle aches, anxiety,
sweating).
In the pivotal clinical study of Suboxone, 342 of 472 patients (72.5 %) reported treatment related
adverse reactions. These reactions are listed in Table 1 by system organ class and frequency (very
common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000 to ≤ 1/100)).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1: Treatment-related undesirable effects reported in the pivotal clinical study of Suboxone (≥
0.1% of Suboxone-treated patients)
Infections and infestations
Common: Infection
Uncommon: Vaginitis
Blood and lymphatic system
disorders
Uncommon: Anaemia, thrombocytopenia, leucopenia, lymphadenopathy,
leukocytosis
Immune system disorders
Uncommon: Allergic reaction
Metabolism and nutrition disorders
Common: Peripheral oedema, weight decreased
Uncommon: Hyperglycaemia, hyperlipemia, hypoglycemia
Psychiatric disorders
Common: Anxiety, nervousness, depression, libido decreased, thinking
abnormal
Uncommon: Drug dependence, amnesia, hostility, speech disorder,
depersonalization, abnormal dream, apathy, euphoria
Nervous system disorders
Very Common: Insomnia
Common: Somnolence, dizziness, paresthesia, hypertonia
Uncommon: Convulsion, agitation, tremor, hyperkinesia
Eye disorders
Common: Lacrimation disorder, amblyopia
Uncommon: Miosis, conjunctivitis
Cardiac disorders
Uncommon: Myocardial infarction, angina pectoris, palpitation, tachycardia,
bradycardia
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Vascular disorders
Common: Vasodilation, hypertension, migraine
Uncommon: Hypotension, heat stroke
Respiratory, thoracic and
mediastinal disorders
Common: Rhinitis, pharyngitis, cough increased
Uncommon: Dyspnoea, asthma, yawn
Gastrointestinal disorders
Very Common: Constipation, nausea
Common: Vomiting, dyspepsia, diarrhoea, anorexia, flatulence
Uncommon: Ulcerative stomatitis, tongue discolouration
Hepatobiliary disorders
Common: Liver function abnormal
Skin and subcutaneous tissue
disorders
Very Common: Sweating
Common: Rash, pruritus, urticaria
Uncommon: Exfoliative dermatitis, acne, skin nodule, alopecia, dry skin
Musculoskeletal, connective tissue
and bone disorders
Common: Arthralgia, myalgia, leg cramps
Uncommon: Arthritis
Renal and urinary disorders
Common: Albuminuria, urine abnormality
Uncommon: Haematuria, kidney calculus, increased creatinine, urinary tract
infection, dysuria, urinary retention
Reproductive system and breast
disorders
Uncommon: Impotence, amenorrhoea, abnormal ejaculation, menorrhagia,
metrorrhagia
General disorders
Very Common: Withdrawal syndrome, headache
Common: Asthenia, fever, flu syndrome, malaise, accidental injury, chills,
chest pain, abdominal pain, back pain, pain
Injury, poisoning and procedural
complications
Uncommon: Hypothermia
Buprenorphine used alone for treatment of opioid dependency has been associated with the following
symptoms (> 1 %): constipation, headache, insomnia, asthenia, drowsiness, nausea and vomiting,
fainting and dizziness, orthostatic hypotension, and sweating. Other undesirable effects (< 0.1 %) have
been reported in association with buprenorphine alone. These are:
•
respiratory depression (see sections 4.4 and 4.5),
•
hepatic necrosis and hepatitis (see section 4.4),
•
hallucinations,
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•
cases of bronchospasm, angioneurotic oedema and anaphylactic shock.
In cases of intravenous misuse, local reactions, sometimes septic, and potentially serious acute
hepatitis have been reported (see section 4.4).
In patients presenting with marked drug dependence, initial administration of buprenorphine can
produce a withdrawal effect similar to that associated with naloxone.
Spontaneous abortion has been reported with both buprenorphine and buprenorphine-naloxone. It is
not possible to establish a causal relationship, since cases typically involve other drug use or risk
factors for spontaneous abortion (see section 4.6).
A neonatal abstinence syndrome has been reported among newborns of women who have received
buprenorphine during pregnancy. The syndrome may be milder and more protracted than that from
short acting full µ-opioid agonists. The nature of the syndrome may vary depending upon the mother’s
drug use history (see section 4.6).
4.9
Overdose
In the event of 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: Symptomatic treatment of respiratory depression, and standard intensive care measures,
should be implemented. A patent airway and assisted or controlled ventilation must be assured. The
patient should be transferred to an environment within which full resuscitation facilities are available.
Use of an opioid antagonist (i.e., naloxone) is recommended, despite the modest effect it may have in
reversing the respiratory symptoms of buprenorphine compared with its effects on full agonist opioid
agents.
The long duration of action of Suboxone should be taken into consideration when determining the
length of treatment and medical surveillance needed to reverse the effects of an overdose.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in opioid dependence, ATC code: N07B C51.
Mechanism of action:
Buprenorphine is an opioid partial agonist/antagonist which binds to the µ (mu) and κ (kappa)
receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible
properties with the µ receptors, which over a prolonged period, might minimise the need of addicted
patients for drugs.
Opioid agonist ceiling effects were observed during clinical pharmacology studies in opioid-dependent
persons.
Naloxone is an antagonist at µ (mu)-opioid receptors. When administered orally or sublingually in
usual doses to patients experiencing opioid withdrawal, naloxone exhibits little or no pharmacological
effect because of its almost complete first pass metabolism. However, when administered
intravenously to opioid dependent persons, the presence of naloxone in Suboxone produces marked
opioid antagonist effects and opioid withdrawal, thereby deterring intravenous abuse.
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Clinical efficacy:
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. In this trial, 326 heroin-addicted subjects were
randomly assigned to either Suboxone 16 mg per day, 16 mg buprenorphine per day or placebo
tablets. For subjects randomized 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 randomized 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).
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
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 to10 day induction phase, a 16-week maintenance phase and a 7week detoxification phase. Buprenorphine was titrated to maintenance dose by Day 3; active control
doses were titrated more gradually. Based on retention in treatment and the percentage of thriceweekly 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.
5.2
Pharmacokinetic properties
Buprenorphine
Absorption:
Buprenorphine, when taken orally, undergoes first-pass metabolism with N-dealkylation and
glucuroconjugation in the small intestine and the liver. The use of this medicinal product by the oral
route is therefore inappropriate.
Peak plasma concentrations are achieved 90 minutes after sublingual administration. Plasma levels of
buprenorphine increased with the sublingual dose of Suboxone. Both Cmax and AUC of buprenorphine
increased with the increase in dose (in the range of 4-16 mg), although the increase was less than dose
proportional.
Suboxone 4 mg
Suboxone 8 mg
Suboxone 16 mg
Cmax · ng/ml
1.84 (39)
3.0 (51)
5.95 (38)
AUC0-48
hour · ng/ml
12.52 (35)
20.22 (43)
34.89 (33)
Pharmacokinetic Parameter
Distribution:
The absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2 to
5 hours).
Metabolism and elimination:
Buprenorphine is metabolised by 14-N-dealkylation and glucuroconjugation of the parent molecule
and the dealkylated metabolite. Clinical data confirm that CYP3A4 is responsible for the N-
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dealkylation of buprenorphine. N-dealkylbuprenorphine is a µ (mu)-opioid agonist with weak intrinsic
activity.
Elimination of buprenorphine is bi- or tri-exponential, and has a mean half-life from plasma of
32 hours.
Buprenorphine is eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites
(70 %), the rest being eliminated in the urine.
Naloxone
Absorption and distribution:
Following intravenous administration, naloxone is rapidly distributed (distribution half-life
~ 4 minutes). Following oral administration, naloxone is barely detectable in plasma; following
sublingual administration of Suboxone, plasma naloxone concentrations are low and decline rapidly.
Metabolism and elimination:
The medicinal product is metabolized in the liver, primarily by glucuronide conjugation, and excreted
in the urine. Naloxone has a mean half-life from plasma of 1.2 hours.
Special populations:
Elderly: No pharmacokinetic data in elderly patients are available.
Renal impairment: Renal elimination plays a relatively small role (~30 %) in the overall clearance of
Suboxone. No dose modification based on renal function is required but caution is recommended
when dosing subjects with severe renal impairment.
Hepatic impairment: Hepatic elimination plays a relatively large role (~70 %) in the overall clearance
of Suboxone and the action of buprenorphine may be prolonged in subjects with impaired hepatic
clearance. Lower initial Suboxone doses and cautious titration of dosage may be required in patients
with mild to moderate hepatic dysfunction. Suboxone is contraindicated in patients with severe hepatic
dysfunction (see section 4.3).
5.3
Preclinical safety data
The combination of buprenorphine and naloxone has been investigated in acute and repeated dose (up
to 90 days in rats) toxicity studies in animals. No synergistic enhancement of toxicity has been
observed. Undesirable effects were based on the known pharmacological activity of opioid agonistic
and/or antagonistic substances.
The combination (4:1) of buprenorphine hydrochloride and naloxone hydrochloride was not
mutagenic in a bacterial mutation assay (Ames test), and was not clastogenic in an in vitro cytogenetic
assay in human lymphocytes or in an intravenous micronucleus test in the rat.
Reproduction studies by oral administration of buprenorphine: naloxone (ratio 1:1) indicated that
embryolethality occurred in rats in the presence of maternal toxicity at all doses. The lowest dose
studied represented exposure multiples of 1x for buprenorphine and 5x for naloxone at the maximum
human therapeutic dose calculated on a mg/m² basis. No developmental toxicity was observed in
rabbits at maternally toxic doses. Further, no teratogenicity has been observed in either rats or rabbits.
A peri-postnatal study has not been conducted with Suboxone; however, maternal oral administration
of buprenorphine at high doses during gestation and lactation resulted in difficult parturition (possible
as a result of the sedative effect of buprenorphine), high neonatal mortality and a slight delay in the
development of some neurological functions (surface righting reflex and startle response) in neonatal
rats.
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Dietary administration of Suboxone in the rat at dose levels of 500 ppm or greater produced a
reduction in fertility demonstrated by reduced female conception rates. A dietary dose of 100 ppm
(estimated exposure approximately 2.4x for buprenorphine at a human dose of 24 mg Suboxone based
on AUC, plasma levels of naloxone were below the limit of detection in rats) had no adverse effect on
fertility in females.
A 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.
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Lactose monohydrate,
Mannitol,
Maize starch,
Povidone K 30,
Citric acid anhydrous,
Sodium citrate,
Magnesium stearate,
Acesulfame potassium,
Natural lemon and lime flavour.
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
3 years
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
7 tablets in blister packs Nylon/Aluminum/PVC.
28 tablets in blister packs Nylon/Aluminum/PVC.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
Medicines no longer required should not be disposed of via wastewater or the municipal sewage
system. Patients should be instructed to return them to a pharmacy or to ask their pharmacist how to
dispose of them in accordance with the national regulations. These measures will help to protect the
environment.
7.
MARKETING AUTHORISATION HOLDER
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SP Europe
Rue de Stalle, 73
B-1180 Bruxelles
Belgium
8.
MARKETING AUTHORISATION NUMBER(S)
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10.
DATE OF REVISION OF THE TEXT
Detailed information on this product is available on the web-site of the European Medicines Agency
(EMEA) http://www.emea.eu.int/
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1.
NAME OF THE MEDICINAL PRODUCT
Suboxone 8 mg/2 mg sublingual tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 8 mg buprenorphine (as buprenorphine hydrochloride) and 2 mg naloxone (as
naloxone hydrochloride dihydrate).
Excipients:
lactose 168 mg
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Sublingual tablet
White hexagonal biconvex tablets, embossed with a sword logo on one side and “N8” on the reverse
side.
4.
CLINICAL PARTICULARS
4.1
Therapeutic indications
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.
Treatment is intended for use in adults and adolescents over 15 years of age who have agreed to be
treated for addiction.
4.2
Posology and method of administration
Treatment must be under the supervision of a physician experienced in the management of
opiate dependence/addiction.
Each Suboxone sublingual tablet contains buprenorphine and naloxone. Suboxone containing 8 mg
buprenorphine and 2 mg naloxone is referred to as the "8 mg" tablets.
Physicians must warn patients that the sublingual route is the only effective and safe route of
administration for this medicinal product (see section 4.4). Suboxone sublingual tablets are to be
placed under the tongue until dissolved, which usually requires 5 to 10 minutes. The dose is made up
from Suboxone 2 mg/0.5 mg and Suboxone 8 mg/2 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.
Adults:
Baseline liver function tests and documentation of viral hepatitis status is recommended prior to
commencing therapy. Patients who are positive for viral hepatitis, on concomitant medicinal products
(see section 4.5) and/or have existing liver dysfunction are at risk of accelerated liver injury. Regular
monitoring of liver function is recommended (see section 4.4).
Induction:
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Prior to treatment induction, consideration should be given to the type of opioid dependence (i.e. long- or
short-acting opioid), the time since last opioid use and the degree of opioid dependence. To avoid
precipitating withdrawal, induction with Suboxone or buprenorphine only tablets should be undertaken
when objective and clear signs of withdrawal are evident.
Initiation therapy:
The recommended starting dose is one to two tablets of Suboxone 2 mg/0.5 mg sublingual tablets. An
additional one to two tablets of the Suboxone 2 mg/0.5 mg may be administered on day one depending on
the individual patient’s requirement.
Opioid-dependent drug addicts who have not undergone withdrawal: When treatment starts, the first
dose of Suboxone should be taken when signs of withdrawal appear, but not less than 6 hours after the
patient last used opioids (eg. heroin; short acting opioids).
Patients receiving methadone: Before beginning Suboxone therapy, the dose of methadone must be
reduced to a maximum of 30 mg/day. The first dose of Suboxone should be taken when signs of
withdrawal appear, but not less than 24 hours after the patient last used methadone. Buprenorphine
may precipitate symptoms of withdrawal in patients dependent upon methadone.
Dosage adjustment and maintenance: The dose of Suboxone should be increased progressively
according to the clinical effect of the individual patient and should not exceed a maximum single daily
dose of 24 mg. The dosage is titrated according to reassessment of the clinical and psychological
status of the patient and should be made in steps of 2-8 mg.
During the initiation of treatment, daily dispensing of buprenorphine is recommended. After
stabilisation, a reliable patient may be given a supply of Suboxone sufficient for several days of
treatment. It is recommended that the amount of Suboxone be limited to 7 days or according to local
requirements.
Less than daily dosing: After a satisfactory stabilisation has been achieved the frequency of Suboxone
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 8 mg may be given 16 mg on alternate days,
with no dose on the intervening days. However, the dose given on any one day should not exceed
24 mg. In some patients, after a satisfactory stabilisation has been achieved, the frequency of
Suboxone 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 dose on the
intervening days. However, the dose given on any one day should not exceed 24 mg. Patients
requiring a titrated daily dose > 8 mg/day may not find this regimen adequate.
Dosage reduction and termination of treatment: After a satisfactory stabilisation has been achieved, if
the patient agrees, the dosage may be reduced gradually to a lower maintenance dose; in some
favourable cases, treatment may be discontinued. The availability of the sublingual tablet in doses of
2 mg and 8 mg allows for a downward titration of dosage. For patients who may require a lower
buprenorphine dose, buprenorphine 0.4 mg sublingual tablets may be used. Patients should be
monitored following termination of treatment because of the potential for relapse.
Elderly:
No data is available on elderly patients.
Paediatrics:
Suboxone is not recommended for use in children below age 15 years due to lack of data on safety and
efficacy.
Patients with impaired hepatic function:
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The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown.
Since both active substances are extensively metabolized, the plasma levels will be expected to be
higher in patients with moderate and severe hepatic impairment. It is not known whether both active
substances are affected to the same extent.
As Suboxone pharmacokinetics may be altered in patients with hepatic insufficiency, lower initial
doses and careful dose titration in patients with mild to moderate hepatic impairment are
recommended (see section 5.2).
Patients with impaired renal function:
Modification of the Suboxone dose is not required in patients with renal insufficiency. Caution is
recommended when dosing patients with severe renal impairment (CLcr < 30 ml/min) (see section 5.2).
4.3
Contraindications
Suboxone is contraindicated in the following instances:
•
hypersensitivity to buprenorphine, to naloxone, or to any of the excipients,
•
severe respiratory insufficiency,
•
severe hepatic insufficiency,
•
acute alcoholism or delirium tremens.
4.4
Special warnings and precautions for use
Due to the lack of data in adolescents (age 15-<18), Suboxone should be used only with caution in this
age group.
Patients should be closely monitored during the switching period from buprenorphine or methadone to
Suboxone since withdrawal symptoms have been reported.
Diversion:
Diversion refers to the introduction of buprenorphine into the illicit market either by patients or by
individuals who obtain the medicinal product through theft from patients or pharmacies. This
diversion may lead to new addicts using buprenorphine as the primary drug of abuse, with the risks of
overdose, spread of blood borne viral infections, respiratory depression and hepatic injury. Because
the naloxone in the combination tablet precipitated withdrawal in individuals dependent on heroin,
methadone, or other full agonists, Suboxone is expected to be less likely to be diverted for intravenous
use.
Precipitated withdrawal:
When initiating treatment with buprenorphine, the physician must be aware of the partial agonist
profile of buprenorphine and that it can precipitate withdrawal in opioid-dependent patients
particularly if administered less than 6 hours after the last use of heroin or other short acting opioid, or
if administered less than 24 hours after the last dose of methadone (see section 4.2). Conversely,
withdrawal symptoms may also be associated with suboptimal dosing.
The risk of serious undesirable effects such as overdose or treatment dropout is greater if a patient is
under dosed with Suboxone and continues to self medicate withdrawal symptoms with opioids,
alcohol or other sedative-hypnotics in particular benzodiazepines.
Dependence:
Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration produces
dependence of the opioid type.
Discontinuation of treatment may result in a withdrawal syndrome that may be delayed.
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Suboxone may cause drowsiness, particularly when taken together with alcohol or central nervous
system depressants (such as tranquilisers, sedatives or hypnotics) (see section 4.5).
Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may produce
dependence but at a lower level than morphine.
Respiratory depression:
A number of cases of death due to respiratory depression have been reported, particularly when
buprenorphine was used in combination with benzodiazepines (see section 4.5), or when
buprenorphine was not used according to prescribing information.
Deaths have been reported in association with concomitant administration of buprenorphine and other
depressants such as alcohol or other opioids.
Hepatitis and hepatic events:
Cases of acute hepatic injury have been reported in opioid-dependent addicts both in clinical trials and
in post marketing 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 use of other
potentially hepatotoxic medicines, and ongoing injecting drug use may have a causative or
contributory role. These underlying factors must be taken into consideration before prescribing
Suboxone and during treatment. When a hepatic event is suspected, further biological and etiological
evaluation is required. Depending upon the findings, the medicinal product may be discontinued
cautiously so as to prevent withdrawal symptoms and to prevent a return to illicit drug use. If the
treatment is continued, hepatic function should be monitored closely.
As buprenorphine is an opioid, pain as a symptom of a disease may be attenuated.
Athletes must be aware that this medicine may cause a positive reaction to ‘anti-doping’ tests.
As with other opioids, caution is requested in patients using buprenorphine and having head injury,
increased intracranial pressure, hypotension, prostatic hypertrophy or urethral stenosis.
This product should be used with care in patients with: asthma or respiratory insufficiency (cases of
respiratory depression have been reported with buprenorphine); renal insufficiency (30 % of the
administered dose is eliminated by the renal route; thus, renal elimination may be prolonged); hepatic
insufficiency (hepatic metabolism of buprenorphine may be altered) (see section 4.3).
Medicines that inhibit the enzyme CYP3A4 may give rise to increased concentrations of
buprenorphine. A reduction of the Suboxone dose may be needed. Patients already treated with
CYP3A4 inhibitors should have their dose of Suboxone titrated carefully since a reduced dose may be
sufficient in these patients (see section 4.5).
The concomitant use of monoamine oxidase inhibitors (MAOI) might produce exaggeration of the
effects of opioids, based on experience with morphine.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.
4.5
Interaction with other medicinal products and other forms of interaction
Suboxone should not be taken together with:
•
alcoholic drinks or medications containing alcohol, as alcohol increases the sedative effect of
buprenorphine (see section 4.7).
Suboxone should be used cautiously when co-administered with:
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•
benzodiazepines: This combination may result in death due to respiratory depression of central
origin. Therefore, dosages must be limited and this combination must be avoided in cases where
there is a risk of misuse (see section 4.4).
•
other central nervous system depressants, other opioid derivatives (e.g. methadone, analgesics
and antitussives), certain antidepressants, sedative H1-receptor antagonists, barbiturates,
anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances: these
combinations increase central nervous system depression. The reduced level of alertness can
make driving and using machines hazardous.
•
CYP3A4 inhibitors: an interaction study of buprenorphine with ketoconazole (a potent inhibitor
of CYP3A4) resulted in increased Cmax and AUC (area under the curve) of buprenorphine
(approximately 70 % and 50 % 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 or azole antifungals such as ketoconazole or itraconazole).
•
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 coadministered.
To date, no notable interaction has been observed with cocaine, the agent most frequently used by
multi-drug abusers in association with opioids.
4.6
Pregnancy and lactation
Pregnancy: There is very limited experience with buprenorphine/naloxone in pregnant women. Studies
in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is
unknown.
Towards the end of pregnancy high doses of buprenorphine may induce respiratory depression in the
neonate even after a short period of administration. Long-term administration of buprenorphine during
the last three months of pregnancy may cause a withdrawal syndrome in the neonate.
Suboxone should not be used during pregnancy. If it is the prescriber’s opinion that therapy in
pregnancy is required, the use of buprenorphine may be considered according to the local
buprenorphine labeling.
In case pregnancy occurs while on Suboxone treatment, the mother and the unborn child should be
closely monitored and switched to buprenorphine if further treatment is required.
Breast-feeding: It is unknown whether naloxone is excreted in human breast milk. Buprenorphine and
its metabolites are excreted in human breast milk. In rats buprenorphine has been found to inhibit
lactation. Therefore, breast-feeding should be discontinued during treatment with Suboxone.
4.7
Effects on ability to drive and use machines
In general Suboxone has minor to moderate influence on the ability to move safely in traffic, use
machines, or perform other hazardous activities. Suboxone may cause drowsiness, dizziness, or
impaired thinking, particularly when taken together with alcohol or central nervous system
depressants. Therefore caution is advised when performing the above mentioned activities (see
sections 4.4 and 4.5).
4.8
Undesirable effects
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The most common-treatment related undesirable effects reported during clinical trials with Suboxone
were those related to withdrawal symptoms (e.g. abdominal pain, diarrhoea, muscle aches, anxiety,
sweating).
In the pivotal clinical study of Suboxone, 342 of 472 patients (72.5 %) reported treatment related
adverse reactions. These reactions are listed in Table 1 by system organ class and frequency (very
common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000 to ≤ 1/100).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1: Treatment-related undesirable effects reported in the pivotal clinical study of Suboxone (≥
0.1 % of Suboxone-treated patients)
Infections and infestations
Common: Infection
Uncommon: Vaginitis
Blood and lymphatic system
disorders
Uncommon: Anaemia, thrombocytopenia, leucopenia, lymphadenopathy,
leukocytosis
Immune system disorders
Uncommon: Allergic reaction
Metabolism and nutrition disorders
Common: Peripheral oedema, weight decreased
Uncommon: Hyperglycaemia, hyperlipemia, hypoglycemia
Psychiatric disorders
Common: Anxiety, nervousness, depression, libido decreased, thinking
abnormal
Uncommon: Drug dependence, amnesia, hostility, speech disorder,
depersonalization, abnormal dream, apathy, euphoria
Nervous system disorders
Very Common: Insomnia
Common: Somnolence, dizziness, paresthesia, hypertonia
Uncommon: Convulsion, agitation, tremor, hyperkinesia
Eye disorders
Common: Lacrimation disorder, amblyopia
Uncommon: Miosis, conjunctivitis
Cardiac disorders
Uncommon: Myocardial infarction, angina pectoris, palpitation, tachycardia,
bradycardia
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Vascular disorders
Common: Vasodilation, hypertension, migraine
Uncommon: Hypotension, heat stroke
Respiratory, thoracic and
mediastinal disorders
Common: Rhinitis, pharyngitis, cough increased
Uncommon: Dyspnoea, asthma, yawn
Gastrointestinal disorders
Very Common: Constipation, nausea
Common: Vomiting, dyspepsia, diarrhoea, anorexia, flatulence
Uncommon: Ulcerative stomatitis, tongue discolouration
Hepatobiliary disorders
Common: Liver function abnormal
Skin and subcutaneous tissue
disorders
Very Common: Sweating
Common: Rash, pruritus, urticaria
Uncommon: Exfoliative dermatitis, acne, skin nodule, alopecia, dry skin
Musculoskeletal, connective tissue
and bone disorders
Common: Arthralgia, myalgia, leg cramps
Uncommon: Arthritis
Renal and urinary disorders
Common: Albuminuria, urine abnormality
Uncommon: Haematuria, kidney calculus, increased creatinine, urinary tract
infection, dysuria, urinary retention
Reproductive system and breast
disorders
Uncommon: Impotence, amenorrhoea, abnormal ejaculation, menorrhagia,
metrorrhagia
General disorders
Very Common: Withdrawal syndrome, headache
Common: Asthenia, fever, flu syndrome, malaise, accidental injury, chills,
chest pain, abdominal pain, back pain, pain
Injury, poisoning and procedural
complications
Uncommon: Hypothermia
Buprenorphine used alone for treatment of opioid dependency has been associated with the following
symptoms (> 1 %): constipation, headache, insomnia, asthenia, drowsiness, nausea and vomiting,
fainting and dizziness, orthostatic hypotension, and sweating. Other undesirable effects (< 0.1 %) have
been reported in association with buprenorphine alone. These are:
•
respiratory depression (see sections 4.4 and 4.5),
•
hepatic necrosis and hepatitis (see section 4.4),
•
hallucinations,
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•
cases of bronchospasm, angioneurotic oedema and anaphylactic shock.
In cases of intravenous misuse, local reactions, sometimes septic, and potentially serious acute
hepatitis have been reported (see section 4.4).
In patients presenting with marked drug dependence, initial administration of buprenorphine can
produce a withdrawal effect similar to that associated with naloxone.
Spontaneous abortion has been reported with both buprenorphine and buprenorphine-naloxone. It is
not possible to establish a causal relationship, since cases typically involve other drug use or risk
factors for spontaneous abortion (see section 4.6).
A neonatal abstinence syndrome has been reported among newborns of women who have received
buprenorphine during pregnancy. The syndrome may be milder and more protracted than that from
short acting full µ-opioid agonists. The nature of the syndrome may vary depending upon the mother’s
drug use history (see section 4.6).
4.9
Overdose
In the event of 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: Symptomatic treatment of respiratory depression, and standard intensive care measures,
should be implemented. A patent airway and assisted or controlled ventilation must be assured. The
patient should be transferred to an environment within which full resuscitation facilities are available.
Use of an opioid antagonist (i.e., naloxone) is recommended, despite the modest effect it may have in
reversing the respiratory symptoms of buprenorphine compared with its effects on full agonist opioid
agents.
The long duration of action of Suboxone should be taken into consideration when determining the
length of treatment and medical surveillance needed to reverse the effects of an overdose.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in opioid dependence, ATC code: N07B C51.
Mechanism of action:
Buprenorphine is an opioid partial agonist/antagonist which binds to the µ (mu) and κ (kappa)
receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible
properties with the µ receptors, which over a prolonged period, might minimise the need of addicted
patients for drugs.
Opioid agonist ceiling effects were observed during clinical pharmacology studies in opioid-dependent
persons.
Naloxone is an antagonist at µ (mu)-opioid receptors. When administered orally or sublingually in
usual doses to patients experiencing opioid withdrawal, naloxone exhibits little or no pharmacological
effect because of its almost complete first pass metabolism. However, when administered
intravenously to opioid dependent persons, the presence of naloxone in Suboxone produces marked
opioid antagonist effects and opioid withdrawal, thereby deterring intravenous abuse.
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Clinical efficacy:
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. In this trial, 326 heroin-addicted subjects were
randomly assigned to either Suboxone 16 mg per day, 16 mg buprenorphine per day or placebo
tablets. For subjects randomized 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 randomized 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).
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
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 to10 day induction phase, a 16-week maintenance phase and a 7week detoxification phase. Buprenorphine was titrated to maintenance dose by Day 3; active control
doses were titrated more gradually. Based on retention in treatment and the percentage of thriceweekly 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.
5.2
Pharmacokinetic properties
Buprenorphine
Absorption:
Buprenorphine, when taken orally, undergoes first-pass metabolism with N-dealkylation and
glucuroconjugation in the small intestine and the liver. The use of this medicinal product by the oral
route is therefore inappropriate.
Peak plasma concentrations are achieved 90 minutes after sublingual administration. Plasma levels of
buprenorphine increased with the sublingual dose of Suboxone. Both Cmax and AUC of buprenorphine
increased with the increase in dose (in the range of 4-16 mg), although the increase was less than dose
proportional.
Suboxone 4 mg
Suboxone 8 mg
Suboxone 16 mg
Cmax · ng/ml
1.84 (39)
3.0 (51)
5.95 (38)
AUC0-48
hour · ng/ml
12.52 (35)
20.22 (43)
34.89 (33)
Pharmacokinetic Parameter
Distribution:
The absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2 to
5 hours).
Metabolism and elimination:
Buprenorphine is metabolised by 14-N-dealkylation and glucuroconjugation of the parent molecule
and the dealkylated metabolite. Clinical data confirm that CYP3A4 is responsible for the N-
22/48
dealkylation of buprenorphine. N-dealkylbuprenorphine is a µ (mu)-opioid agonist with weak intrinsic
activity.
Elimination of buprenorphine is bi- or tri-exponential, and has a mean half-life from plasma of
32 hours.
Buprenorphine is eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites
(70 %), the rest being eliminated in the urine.
Naloxone
Absorption and distribution:
Following intravenous administration, naloxone is rapidly distributed (distribution half-life
~ 4 minutes). Following oral administration, naloxone is barely detectable in plasma; following
sublingual administration of Suboxone, plasma naloxone concentrations are low and decline rapidly.
Metabolism and elimination:
The medicinal product is metabolized in the liver, primarily by glucuronide conjugation, and excreted
in the urine. Naloxone has a mean half-life from plasma of 1.2 hours.
Special populations:
Elderly: No pharmacokinetic data in elderly patients are available.
Renal impairment: Renal elimination plays a relatively small role (~30 %) in the overall clearance of
Suboxone. No dose modification based on renal function is required but caution is recommended
when dosing subjects with severe renal impairment.
Hepatic impairment: Hepatic elimination plays a relatively large role (~70 %) in the overall clearance
of Suboxone and the action of buprenorphine may be prolonged in subjects with impaired hepatic
clearance. Lower initial Suboxone doses and cautious titration of dosage may be required in patients
with mild to moderate hepatic dysfunction. Suboxone is contraindicated in patients with severe hepatic
dysfunction (see section 4.3).
5.3
Preclinical safety data
The combination of buprenorphine and naloxone has been investigated in acute and repeated dose (up
to 90 days in rats) toxicity studies in animals. No synergistic enhancement of toxicity has been
observed. Undesirable effects were based on the known pharmacological activity of opioid agonistic
and/or antagonistic substances.
The combination (4:1) of buprenorphine hydrochloride and naloxone hydrochloride was not
mutagenic in a bacterial mutation assay (Ames test), and was not clastogenic in an in vitro cytogenetic
assay in human lymphocytes or in an intravenous micronucleus test in the rat.
Reproduction studies by oral administration of buprenorphine: naloxone (ratio 1:1) indicated that
embryolethality occurred in rats in the presence of maternal toxicity at all doses. The lowest dose
studied represented exposure multiples of 1x for buprenorphine and 5x for naloxone at the maximum
human therapeutic dose calculated on a mg/m² basis. No developmental toxicity was observed in
rabbits at maternally toxic doses. Further, no teratogenicity has been observed in either rats or rabbits.
A peri-postnatal study has not been conducted with Suboxone; however, maternal oral administration
of buprenorphine at high doses during gestation and lactation resulted in difficult parturition (possible
as a result of the sedative effect of buprenorphine), high neonatal mortality and a slight delay in the
development of some neurological functions (surface righting reflex and startle response) in neonatal
rats.
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Dietary administration of Suboxone in the rat at dose levels of 500 ppm or greater produced a
reduction in fertility demonstrated by reduced female conception rates. A dietary dose of 100 ppm
(estimated exposure approximately 2.4x for buprenorphine at a human dose of 24 mg Suboxone based
on AUC, plasma levels of naloxone were below the limit of detection in rats) had no adverse effect on
fertility in females.
A 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.
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Lactose monohydrate,
Mannitol,
Maize starch,
Povidone K 30,
Citric acid anhydrous,
Sodium citrate,
Magnesium stearate,
Acesulfame potassium,
Natural lemon and lime flavour.
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
3 years
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
7 tablets in blister packs Nylon/Aluminum/PVC.
28 tablets in blister packs Nylon/Aluminum/PVC.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
Medicines no longer required should not be disposed of via wastewater or the municipal sewage
system. Patients should be instructed to return them to a pharmacy or to ask their pharmacist how to
dispose of them in accordance with the national regulations. These measures will help to protect the
environment.
7.
MARKETING AUTHORISATION HOLDER
24/48
SP Europe
Rue de Stalle, 73
B-1180 Bruxelles
Belgium
8.
MARKETING AUTHORISATION NUMBER(S)
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10.
DATE OF REVISION OF THE TEXT
Detailed information on this product is available on the web-site of the European Medicines Agency
(EMEA) http://www.emea.eu.int/
25/48
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
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A.
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Reckitt Benckiser Healthcare (UK) Ltd
Dansom Lane
Hull, East Yorkshire
HU8 7DS
United Kingdom
B.
CONDITIONS OF THE MARKETING AUTHORISATION
•
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON
THE MARKETING AUTHORISATION HOLDER
Medicinal product subject to special and restricted medical prescription (See Annex I: Summary of
Product Characteristics, section 4.2).
Substitution treatment for opioid drug dependence is intended for use in adults and adolescents over
15 years of age who have agreed to be treated for addiction, within a framework of medical, social and
psychological treatment, by physicians experienced in the treatment of opiate dependence/addiction.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The MAH must ensure that the system of pharmacovigilance is in place and functioning before the
product is placed on the market and for as long as the marketed product remains in use.
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan.
An updated Risk Management Plan should be provided as per the CHMP Guideline on Risk
Management Systems for medicinal products for human use.
27/48
ANNEX III
LABELLING AND PACKAGE LEAFLET
28/48
A. LABELLING
29/48
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
PACK OF 7 and 28 TABLETS 2 MG STRENGTH
1.
NAME OF THE MEDICINAL PRODUCT
Suboxone 2 mg/0.5 mg sublingual tablets
buprenorphine / naloxone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each sublingual tablet contains 2 mg buprenorphine as buprenorphine hydrochloride and 0.5 mg
naloxone as naloxone hydrochloride dihydrate.
3.
LIST OF EXCIPIENTS
Includes lactose monohydrate.
See leaflet for further information.
4.
PHARMACEUTICAL FORM AND CONTENTS
7 sublingual tablets
28 sublingual tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Sublingual use
Do not swallow.
Keep the tablet under your tongue until it dissolves.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
30/48
10.
SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
SP Europe
Rue de Stalle 73
B-1180 Bruxelles, Belgium
12.
MARKETING AUTHORISATION NUMBER(S)
EU/0/00/000/000
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Suboxone 2 mg/0.5 mg
31/48
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
PACK OF 7 and 28 TABLETS 8 MG STRENGTH
1.
NAME OF THE MEDICINAL PRODUCT
Suboxone 8 mg/2 mg sublingual tablets
buprenorphine / naloxone
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each sublingual tablet contains 8 mg buprenorphine as buprenorphine hydrochloride and 2 mg
naloxone as naloxone hydrochloride dihydrate.
3.
LIST OF EXCIPIENTS
Includes lactose monohydrate.
See leaflet for further information.
4.
PHARMACEUTICAL FORM AND CONTENTS
7 sublingual tablets
28 sublingual tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Sublingual use
Do not swallow.
Keep the tablet under your tongue until it dissolves.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
32/48
10.
SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11.
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
SP Europe
Rue de Stalle 73
B-1180 Bruxelles, Belgium
12.
MARKETING AUTHORISATION NUMBER(S)
EU/0/00/000/000
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Suboxone 8 mg/2 mg
33/48
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
PACK OF 7 and 28 TABLETS 2 MG STRENGTH
1.
NAME OF THE MEDICINAL PRODUCT
Suboxone 2 mg/0.5 mg sublingual tablets
buprenorphine / naloxone
2.
NAME OF THE MARKETING AUTHORISATION HOLDER
SP Europe
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
34/48
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
PACK OF 7 and 28 TABLETS 8 MG STRENGTH
1.
NAME OF THE MEDICINAL PRODUCT
Suboxone 8 mg/2 mg sublingual tablets
buprenorphine / naloxone
2.
NAME OF THE MARKETING AUTHORISATION HOLDER
SP Europe
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
35/48
B. PACKAGE LEAFLET
36/48
PACKAGE LEAFLET: INFORMATION FOR THE USER
Suboxone 2 mg/0.5 mg sublingual tablets
buprenorphine / naloxone
Read all of this leaflet carefully before you start taking this medicine.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Suboxone is and what it is used for
2.
Before you take Suboxone
3.
How to take Suboxone
4.
Possible side effects
5
How to store Suboxone
6.
Further information
1.
WHAT SUBOXONE IS AND WHAT IT IS USED FOR
Medicinal product used in opioid dependence.
Suboxone is part of a medical, social and psychological treatment program for patients addicted to
opiate (narcotic) drugs. Treatment is prescribed and monitored by physicians who are specialists in the
treatment of drug dependence.
Treatment with Suboxone sublingual tablets is intended for use in adults and adolescents over 15 years
of age.
2.
BEFORE YOU TAKE SUBOXONE
Do not take Suboxone
if you are allergic (hypersensitive) to buprenorphine, naloxone or any of the other ingredients of
Suboxone,
if you have serious breathing problems,
if you have serious problems with your liver,
if you are intoxicated due to alcohol or have delirium tremens.
Take special care with Suboxone
Some people have died from respiratory failure (inability to breathe) because they misused
buprenorphine or took it while in combination with other Central Nervous System depressants, such as
alcohol, benzodiazepines (tranquilisers), or other opioids.
Cases of acute hepatic injury (liver problems) have been reported in a context of misuse, especially by
intravenous route and at a high dose. These injuries could be due to special conditions as viral
infections (chronic C hepatitis), alcohol abuse, anorexia, or medicines association (for example:
antiretroviral nucleoside analogues, acetylsalicylic acid (aspirin), amiodarone, isoniazid, valproate). If
you have symptoms of severe fatigue, itching, or if your skin or eyes look yellow, tell your doctor
immediately, so that you can receive the proper treatment.
37/48
This product can cause withdrawal symptoms if you take it less than six hours after you use a narcotic
(e.g. morphine, heroin) or less than 24 hours after you use methadone.
This product can cause sleepiness which may be increased by alcohol or anti-anxiety medicines.
Advise your physician in case of:
recent head injury or brain disease,
decrease of blood pressure,
in men: urinary disorders (especially linked to enlarged prostate).
This medicinal product may mask pain reflecting some diseases. Do not forget to advise your
physician if you take this medicine.
This product may cause your blood pressure to drop suddenly, causing you to feel dizzy if you get up
too quickly from sitting or lying down.
This product can cause dependence.
Athletes should be aware that this medicine, due to its active substance, may cause a positive reaction
to “anti-doping tests”.
Advise your physician in case of:
asthma or other breathing problems,
kidney disease,
liver disease.
Using other medicines
Using other medicines may increase the undesirable effects of buprenorphine and use of these
medicines must be carefully monitored:
•
tranquilizers
•
anti-anxiety medicines
•
anti-depressants
•
benzodiazepines
•
some medicines used to treat high blood pressure.
If your physician prescribes benzodiazepines, you must not take more than the prescribed dose. Taking
this product with benzodiazepines (medicines used to treat anxiety or sleep disorders) may cause death
due to respiratory failure.
The following medicines may increase the buprenorphine blood concentrations, so concomitant use of
these medicines together with Suboxone should be closely monitored and could require in some cases
a dose reduction by your doctor:
•
anti-retrovirals (ritonavir, nelfinavir, indinavir)
•
ketoconazole
•
itraconazole
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Using Suboxone with food and drink
Do not take Suboxone together with alcoholic beverages as alcohol may possibly increase drowsiness
induced by Suboxone.
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
38/48
You should not use Suboxone during pregnancy. Tell your doctor if you are pregnant or intend to
become pregnant. He will decide if your treatment should be continued with an alternative medication.
Since this product will pass into your milk and may adversely affect the breast-fed child, you should
discontinue breast-feeding while taking Suboxone.
Driving and using machines
Suboxone may cause drowsiness. If you feel tired, do not drive a motor vehicle or operate machinery.
Important information about some of the ingredients of Suboxone
Suboxone contains lactose. If you have been told by your doctor that you have intolerance to some
sugars, contact your doctor before taking this medicinal product.
3.
HOW TO TAKE SUBOXONE
Sublingual route is the only efficacious administration route for this product. Do not swallow the
tablets.
Keep the tablet dose under your tongue until it dissolves. This may take 5-10 minutes.
Take the dose once a day.
Your doctor will determine the best dose for you. During your treatment, the doctor may adjust the
dose, depending upon your response. To get the greatest benefit from taking Suboxone, you must tell
your doctor about all the medicines you are taking, including alcohol, medicines containing alcohol,
street drugs, and any prescription medicine you are taking that had not been prescribed to you by your
doctor.
Treatment duration
The length of treatment will be determined individually by your doctor.
After a time of successful treatment, the doctor may reduce the dose gradually to a lower maintenance
dose. Depending on your condition, the Suboxone dose may continue to be reduced under careful
medical supervision, until eventually it may be stopped.
Do not change the treatment in any way or stop treatment without the agreement of the doctor who is
treating you.
The effectiveness of this treatment depends:
on the dose,
in combination with the associated medical, psychological and social treatment.
If you have the impression that the effect of Suboxone is too strong or too weak, talk to your doctor or
pharmacist.
If you use more Suboxone than you should
In case of overdose of buprenorphine, you must go or be taken immediately to an emergency centre or
hospital for treatment.
Advise immediately your doctor or your pharmacist.
If you forget to use Suboxone
Contact your doctor.
If you stop using Suboxone
Stopping treatment suddenly may cause withdrawal symptoms.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
39/48
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Suboxone can cause side effects, although not everybody gets them.
After the first dose of Suboxone, you may have some opiate withdrawal symptoms.
Very common side effects (occurring in at least 1 in 10 patients) that may occur with Suboxone are:
insomnia, constipation, nausea, sweating, headache, withdrawal syndrome.
Common side effects (occurring in at least 1 in 100 patients) that may occur during treatment with
Suboxone are: weight loss, swelling (hands and feet), tiredness, drowsiness, anxiety, nervousness,
tingling, depression, decreased sexual drive, muscle spasms, abnormal thinking, tearing disorder,
blurred vision, flushing, increased blood pressure, migraines, runny nose, sore throat and painful
swallowing, increased cough, upset stomach, diarrhoea, abnormal liver function, loss of appetite,
flatulence, vomiting, rash, itching, hives, pain, joint pain, muscle pain, leg cramps, impotence, urine
abnormality, abdominal pain, back pain, weakness, infection, chills, chest pain, fever, flu syndrome,
feeling of general discomfort, accidental injury, faintness and dizziness, drop in blood pressure on
changing position from sitting or lying down to standing.
Uncommon side effects (occurring in at least 1 in 1,000 patients) with Suboxone are: swollen glands
(lymph nodes), agitation, tremor, abnormal dream, excessive muscle activity, depersonalization (not
feeling like yourself), medicine dependence, amnesia (memory disturbance), loss of interest,
exaggerated feeling of well being, convulsion (fits), speech disorder, small pupil size, problems with
urination, conjunctivitis, rapid or slow heart beat, low blood pressure, palpitations, myocardial
infarction (heart attack), shortness of breath, asthma, yawning, pain and sores in mouth, tongue
discolouration, acne, skin nodule, hair loss, dry or scaling skin, inflammation of joints, urinary tract
infection, blood in urine, abnormal ejaculation, menstrual or vaginal problems, kidney stone,
sensitivity to heat or cold, allergic reaction, feelings of hostility.
Rarely (occurring in at least 1 in 10,000 patients), the following have occurred with buprenorphine
alone:
respiratory depression (severe difficulty in breathing) - see “Take special care with Suboxone”,
liver problems with or without jaundice- see “Take special care with Suboxone”,
hallucinations.
Misusing this medicine by injecting it can cause withdrawal symptoms, infections, other skin reactions
and potentially serious liver problems - see “Take special care with Suboxone”.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE SUBOXONE
Keep out of the reach and sight of children.
Do not use Suboxone after the expiry date which is stated on the carton. The expiry date refers to the
last day of that month.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
40/48
6.
FURTHER INFORMATION
What Suboxone contains
-
The active substance is buprenorphine and naloxone. Each tablet contains 2 mg buprenorphine
as buprenorphine hydrochloride and 0.5 mg naloxone as naloxone hydrochloride dihydrate.
The other ingredients are lactose monohydrate, mannitol, maize starch, povidone K30, citric
acid anhydrous, sodium citrate, magnesium stearate, acesulfame potassium and natural lemon
and lime flavour.
What Suboxone looks like and contents of the pack
Sublingual tablets, white hexagonal biconvex tablets, embossed with a sword logo on one side and
“N2” on the reverse side, packed in packs of 7 and 28 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: SP Europe, Rue de Stalle 73, B-1180 Bruxelles, Belgium.
Manufacturer: Reckitt Benckiser Healthcare (UK) Ltd, Dansom Lane, Hull, East Yorkshire HU8 7DS,
United Kingdom.
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Rue de Stalle/Stallestraat 73
B-1180 Bruxelles/Brussel/Brüssel
Tél/Tel: + 32-(0)2 370 92 11
Luxembourg/Luxemburg
Rue de Stalle 73
B-1180 Bruxelles/Brüssel
Belgique/Belgien
Tél/Tel: + 32-(0)2 370 92 11
Česká republika
Na Příkopě 25
CZ-110 00 Praha 1
Tel: + 420 221771250
Magyarország
Alkotás u. 53.
H-1123 Budapest
Tel.: + 36 1 457-8500
Danmark
Hvedemarken 12
DK-3520 Farum
Tlf: + 45-44 39 50 00
Malta
168 Christopher Street
MT-VLT02 Valletta
Tel: + 356-21 23 21 75
Deutschland
Thomas-Dehler-Straße 27
D-81737 München
Tel: + 49-(0)89 627 31-0
Nederland
Maarssenbroeksedijk 4
NL-3542 DN Utrecht
Tel: + 31-(0)30 240 88 88
Eesti
Järvevana tee 9
EE-11314 Tallinn
Tel: + 372 654 96 86
Norge
Ankerveien 209
N-1359 Eiksmarka
Tlf: + 47 67 16 64 50
Ελλάδα
Αγίου ∆ηµητρίου 63
GR-174 55 Άλιµος
Österreich
Badener Strasse 23
A-2514 Traiskirchen
41/48
Tηλ: + 30-210 98 97 300
Tel: + 43-(0)2252 502-0
España
Km. 36, Ctra. Nacional I
E-28750 San Agustín de Guadalix – Madrid
Tel: + 34-91 848 85 00
Polska
Al. Jerozolimskie 195a
PL-02-222 Warszawa
Tel.: + 48-(0)22 478 41 50
France
92 rue Baudin
F-92300 Levallois-Perret
Tél: + 33-(0)1 41 06 35 00
Portugal
Rua Agualva dos Açores 16
P-2735-557 Agualva-Cacém
Tel: + 351-21 433 93 00
Ireland
Shire Park
Welwyn Garden City
Hertfordshire AL7 1TW
Tel: + 44-(0)1 707 363 636
Slovenija
Dunajska 22
SI-1000 Ljubljana
Tel: + 386 01 3001070
Ísland
Hörgatún 2
IS-210 Garðabær
Sími: + 354 535 70 00
Slovenská republika
Strakova 5
SK-811 01 Bratislava
Tel: + 421 (2) 5920 2712
Italia
Centro Direzionale Milano Due
Palazzo Borromini
I-20090 Segrate (Milano)
Tel: + 39-02 21018.1
Suomi/Finland
PL 3/PB 3
FIN-02201 Espoo/Esbo
Puh/Tel: + 358-(0)20 7570 300
Κύπρος
Οδός Αγίου Νικολάου, 8
CY-1055 Λευκωσία
Τηλ: + 357-22 757188
Sverige
Box 27190
S-102 52 Stockholm
Tel: + 46-(0)8 522 21 500
Latvija
Vāgnera iela 13
Rīga LV-1050
Tel: + 371-7 21 38 25
United Kingdom
Shire Park
Welwyn Garden City
Hertfordshire AL7 1TW - UK
Tel: + 44-(0)1 707 363 636
Lietuva
Kęstučio g. 65/40
LT-08124 Vilnius
Tel. + 370 52 638 446
This leaflet was last approved on
Detailed information on this product is available on the web-site of the European Medicines Agency
(EMEA) http://www.emea.eu.int/
42/48
PACKAGE LEAFLET: INFORMATION FOR THE USER
Suboxone 8 mg/2 mg sublingual tablets
buprenorphine / naloxone
Read all of this leaflet carefully before you start taking this medicine.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Suboxone is and what it is used for
2.
Before you take Suboxone
3.
How to take Suboxone
4.
Possible side effects
5
How to store Suboxone
6.
Further information
1.
WHAT SUBOXONE IS AND WHAT IT IS USED FOR
Medicinal product used in opioid dependence.
Suboxone is part of a medical, social and psychological treatment program for patients addicted to
opiate (narcotic) drugs. Treatment is prescribed and monitored by physicians who are specialists in the
treatment of drug dependence.
Treatment with Suboxone sublingual tablets is intended for use in adults and adolescents over 15 years
of age.
2.
BEFORE YOU TAKE SUBOXONE
Do not take Suboxone
if you are allergic (hypersensitive) to buprenorphine, naloxone or any of the other ingredients of
Suboxone,
if you have serious breathing problems,
if you have serious problems with your liver,
if you are intoxicated due to alcohol or have delirium tremens.
Take special care with Suboxone
Some people have died from respiratory failure (inability to breathe) because they misused
buprenorphine or took it while in combination with other Central Nervous System depressants, such as
alcohol, benzodiazepines (tranquilisers), or other opioids.
Cases of acute hepatic injury (liver problems) have been reported in a context of misuse, especially by
intravenous route and at a high dose. These injuries could be due to special conditions as viral
infections (chronic C hepatitis), alcohol abuse, anorexia, or medicines association (for example:
antiretroviral nucleoside analogues, acetylsalicylic acid (aspirin), amiodarone, isoniazid, valproate). If
you have symptoms of severe fatigue, itching, or if your skin or eyes look yellow, tell your doctor
immediately, so that you can receive the proper treatment.
43/48
This product can cause withdrawal symptoms if you take it less than six hours after you use a narcotic
(e.g. morphine, heroin) or less than 24 hours after you use methadone.
This product can cause sleepiness which may be increased by alcohol or anti-anxiety medicines.
Advise your physician in case of:
recent head injury or brain disease,
decrease of blood pressure,
in men: urinary disorders (especially linked to enlarged prostate).
This medicinal product may mask pain reflecting some diseases. Do not forget to advise your
physician if you take this medicine.
This product may cause your blood pressure to drop suddenly, causing you to feel dizzy if you get up
too quickly from sitting or lying down.
This product can cause dependence.
Athletes should be aware that this medicine, due to its active substance, may cause a positive reaction
to “anti-doping tests”.
Advise your physician in case of:
asthma or other breathing problems,
kidney disease,
liver disease.
Using other medicines
Using other medicines may increase the undesirable effects of buprenorphine and use of these
medicines must be carefully monitored:
•
tranquilizers
•
anti-anxiety medicines
•
anti-depressants
•
benzodiazepines
•
some medicines used to treat high blood pressure.
If your physician prescribes benzodiazepines, you must not take more than the prescribed dose. Taking
this product with benzodiazepines (medicines used to treat anxiety or sleep disorders) may cause death
due to respiratory failure.
The following medicines may increase the buprenorphine blood concentrations, so concomitant use of
these medicines together with Suboxone should be closely monitored and could require in some cases
a dose reduction by your doctor:
•
anti-retrovirals (ritonavir, nelfinavir, indinavir)
•
ketoconazole
•
itraconazole
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Using Suboxone with food and drink
Do not take Suboxone together with alcoholic beverages as alcohol may possibly increase drowsiness
induced by Suboxone.
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
44/48
You should not use Suboxone during pregnancy. Tell your doctor if you are pregnant or intend to
become pregnant. He will decide if your treatment should be continued with an alternative medication.
Since this product will pass into your milk and may adversely affect the breast-fed child, you should
discontinue breast-feeding while taking Suboxone.
Driving and using machines
Suboxone may cause drowsiness. If you feel tired, do not drive a motor vehicle or operate machinery.
Important information about some of the ingredients of Suboxone
Suboxone contains lactose. If you have been told by your doctor that you have intolerance to some
sugars, contact your doctor before taking this medicinal product.
3.
HOW TO TAKE SUBOXONE
Sublingual route is the only efficacious administration route for this product. Do not swallow the
tablets.
Keep the tablet dose under your tongue until it dissolves. This may take 5-10 minutes.
Take the dose once a day.
Your doctor will determine the best dose for you. During your treatment, the doctor may adjust the
dose, depending upon your response. To get the greatest benefit from taking Suboxone, you must tell
your doctor about all the medicines you are taking, including alcohol, medicines containing alcohol,
street drugs, and any prescription medicine you are taking that had not been prescribed to you by your
doctor.
Treatment duration
The length of treatment will be determined individually by your doctor.
After a time of successful treatment, the doctor may reduce the dose gradually to a lower maintenance
dose. Depending on your condition, the Suboxone dose may continue to be reduced under careful
medical supervision, until eventually it may be stopped.
Do not change the treatment in any way or stop treatment without the agreement of the doctor who is
treating you.
The effectiveness of this treatment depends:
on the dose,
in combination with the associated medical, psychological and social treatment.
If you have the impression that the effect of Suboxone is too strong or too weak, talk to your doctor or
pharmacist.
If you use more Suboxone than you should
In case of overdose of buprenorphine, you must go or be taken immediately to an emergency centre or
hospital for treatment.
Advise immediately your doctor or your pharmacist.
If you forget to use Suboxone
Contact your doctor.
If you stop using Suboxone
Stopping treatment suddenly may cause withdrawal symptoms.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
45/48
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Suboxone can cause side effects, although not everybody gets them.
After the first dose of Suboxone, you may have some opiate withdrawal symptoms.
Very common side effects (occurring in at least 1 in 10 patients) that may occur with Suboxone are:
insomnia, constipation, nausea, sweating, headache, withdrawal syndrome.
Common side effects (occurring in at least 1 in 100 patients) that may occur during treatment with
Suboxone are: weight loss, swelling (hands and feet), tiredness, drowsiness, anxiety, nervousness,
tingling, depression, decreased sexual drive, muscle spasms, abnormal thinking, tearing disorder,
blurred vision, flushing, increased blood pressure, migraines, runny nose, sore throat and painful
swallowing, increased cough, upset stomach, diarrhoea, abnormal liver function, loss of appetite,
flatulence, vomiting, rash, itching, hives, pain, joint pain, muscle pain, leg cramps, impotence, urine
abnormality, abdominal pain, back pain, weakness, infection, chills, chest pain, fever, flu syndrome,
feeling of general discomfort, accidental injury, faintness and dizziness, drop in blood pressure on
changing position from sitting or lying down to standing.
Uncommon side effects (occurring in at least 1 in 1,000 patients) with Suboxone are: swollen glands
(lymph nodes), agitation, tremor, abnormal dream, excessive muscle activity, depersonalization (not
feeling like yourself), medicine dependence, amnesia (memory disturbance), loss of interest,
exaggerated feeling of well being, convulsion (fits), speech disorder, small pupil size, problems with
urination, conjunctivitis, rapid or slow heart beat, low blood pressure, palpitations, myocardial
infarction (heart attack), shortness of breath, asthma, yawning, pain and sores in mouth, tongue
discolouration, acne, skin nodule, hair loss, dry or scaling skin, inflammation of joints, urinary tract
infection, blood in urine, abnormal ejaculation, menstrual or vaginal problems, kidney stone,
sensitivity to heat or cold, allergic reaction, feelings of hostility.
Rarely (occurring in at least 1 in 10,000 patients), the following have occurred with buprenorphine
alone:
respiratory depression (severe difficulty in breathing) - see “Take special care with Suboxone”,
liver problems with or without jaundice- see “Take special care with Suboxone”,
hallucinations.
Misusing this medicine by injecting it can cause withdrawal symptoms, infections, other skin reactions
and potentially serious liver problems - see “Take special care with Suboxone”.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE SUBOXONE
Keep out of the reach and sight of children.
Do not use Suboxone after the expiry date which is stated on the carton. The expiry date refers to the
last day of that month.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
46/48
6.
FURTHER INFORMATION
What Suboxone contains
-
The active substance is buprenorphine and naloxone. Each tablet contains 8 mg buprenorphine
as buprenorphine hydrochloride and 2 mg naloxone as naloxone hydrochloride dihydrate.
The other ingredients are lactose monohydrate, mannitol, maize starch, povidone K30, citric
acid anhydrous, sodium citrate, magnesium stearate, acesulfame potassium and natural lemon
and lime flavour.
What Suboxone looks like and contents of the pack
Sublingual tablets, white hexagonal biconvex tablets, embossed with a sword logo on one side and
“N8” on the reverse side, packed in packs of 7 and 28 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: SP Europe, Rue de Stalle 73, B-1180 Bruxelles, Belgium.
Manufacturer: Reckitt Benckiser Healthcare (UK) Ltd, Dansom Lane, Hull, East Yorkshire HU8 7DS,
United Kingdom.
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Rue de Stalle/Stallestraat 73
B-1180 Bruxelles/Brussel/Brüssel
Tél/Tel: + 32-(0)2 370 92 11
Luxembourg/Luxemburg
Rue de Stalle 73
B-1180 Bruxelles/Brüssel
Belgique/Belgien
Tél/Tel: + 32-(0)2 370 92 11
Česká republika
Na Příkopě 25
CZ-110 00 Praha 1
Tel: + 420 221771250
Magyarország
Alkotás u. 53.
H-1123 Budapest
Tel.: + 36 1 457-8500
Danmark
Hvedemarken 12
DK-3520 Farum
Tlf: + 45-44 39 50 00
Malta
168 Christopher Street
MT-VLT02 Valletta
Tel: + 356-21 23 21 75
Deutschland
Thomas-Dehler-Straße 27
D-81737 München
Tel: + 49-(0)89 627 31-0
Nederland
Maarssenbroeksedijk 4
NL-3542 DN Utrecht
Tel: + 31-(0)30 240 88 88
Eesti
Järvevana tee 9
EE-11314 Tallinn
Tel: + 372 654 96 86
Norge
Ankerveien 209
N-1359 Eiksmarka
Tlf: + 47 67 16 64 50
Ελλάδα
Αγίου ∆ηµητρίου 63
GR-174 55 Άλιµος
Tηλ: + 30-210 98 97 300
Österreich
Badener Strasse 23
A-2514 Traiskirchen
Tel: + 43-(0)2252 502-0
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España
Km. 36, Ctra. Nacional I
E-28750 San Agustín de Guadalix – Madrid
Tel: + 34-91 848 85 00
Polska
Al. Jerozolimskie 195a
PL-02-222 Warszawa
Tel.: + 48-(0)22 478 41 50
France
92 rue Baudin
F-92300 Levallois-Perret
Tél: + 33-(0)1 41 06 35 00
Portugal
Rua Agualva dos Açores 16
P-2735-557 Agualva-Cacém
Tel: + 351-21 433 93 00
Ireland
Shire Park
Welwyn Garden City
Hertfordshire AL7 1TW
Tel: + 44-(0)1 707 363 636
Slovenija
Dunajska 22
SI-1000 Ljubljana
Tel: + 386 01 3001070
Ísland
Hörgatún 2
IS-210 Garðabær
Sími: + 354 535 70 00
Slovenská republika
Strakova 5
SK-811 01 Bratislava
Tel: + 421 (2) 5920 2712
Italia
Centro Direzionale Milano Due
Palazzo Borromini
I-20090 Segrate (Milano)
Tel: + 39-02 21018.1
Suomi/Finland
PL 3/PB 3
FIN-02201 Espoo/Esbo
Puh/Tel: + 358-(0)20 7570 300
Κύπρος
Οδός Αγίου Νικολάου, 8
CY-1055 Λευκωσία
Τηλ: + 357-22 757188
Sverige
Box 27190
S-102 52 Stockholm
Tel: + 46-(0)8 522 21 500
Latvija
Vāgnera iela 13
Rīga LV-1050
Tel: + 371-7 21 38 25
United Kingdom
Shire Park
Welwyn Garden City
Hertfordshire AL7 1TW - UK
Tel: + 44-(0)1 707 363 636
Lietuva
Kęstučio g. 65/40
LT-08124 Vilnius
Tel. + 370 52 638 446
This leaflet was last approved on
Detailed information on this product is available on the web-site of the European Medicines Agency
(EMEA) http://www.emea.eu.int/
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