Date of approval.
Date of revision.
Buprenorphine Naloxone Sublingual Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Buprenorphine Naloxone Sublingual Tablets
Trade name: Suboxone® (SUBOXONE®)
English name: Buprenorphine Hydrochloride and Naloxone Hydrochloride Sublingual Tablets
Hanyu Pinyin：Dingbingnuofei Naluotong Shexia Pian
Ingredients
This product is a compound preparation, containing buprenorphine hydrochloride and naloxone.
Buprenorphine hydrochloride: (2S)-2-[(-)-(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethylidene-3-hydroxy-6-methoxymorphin-7-yl]-3,3-dimethylbutan-2-ol. hydrochloride
Molecular formula: C29H41 NO4.HCl
Molecular weight: 504.1
Naloxone: morphopyran-6-one 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-hydrochloride (5α)-dihydrate; 17-allyl-4,5α-epoxy-3,14-dihydroxymorphopyran-6-one
Hydrochloric acid dihydrate
Structural formula
Molecular formula: C19H21NO4-HCL-2H2O
Molecular weight: 399.87
Excipients include: lactose monohydrate, mannitol, corn starch, povidone K30, anhydrous citric acid, sodium citrate, magnesium stearate, potassium acetyl sulfonate, natural lemon and lime flavor
【Properties】.
This product is white to creamy white hexagonal tablets.
Indications
Used as a replacement therapy for opioid dependence within the framework of medical, social and psychological treatment. Naloxone is added for the purpose of preventing intravenous abuse. This product is indicated for adults or adolescents over 15 years of age who consent to detoxification.
【Specifications】 (1) Buprenorphine 8mg/naloxone 2mg (both in base).
(2) Buprenorphine 2mg/naloxone 0.5mg (both in base)
Dosage
Buprenorphine/naloxone sublingual tablets are recommended as part of a comprehensive treatment regimen for opioid dependence.
Treatment outcome depends on the prescribed dose and monitoring of the patient in conjunction with medical, psychological, social and educational considerations.
Pre-induction considerations
Before initiating treatment, the type of opioid dependence (e.g., long-acting or short-acting opioid), the time since last opioid use, and the degree of opioid dependence should be considered. To avoid precipitating withdrawal, buprenorphine/naloxone or buprenorphine tablets only should be used for induction if the patient shows objective and obvious signs of withdrawal (e.g., mild or moderate withdrawal as indicated by the Clinical Opioid Withdrawal Symptom Scale COWS score).
In patients with heroin or short-acting opioid dependence, the first dose of buprenorphine/naloxone should be initiated after the patient shows signs of withdrawal, and the first dose should be given at least 6 hours before the patient’s last opioid use.
The dose of methadone should be reduced to a maximum of 30 mg per day before starting buprenorphine/naloxone sublingual tablets in patients on methadone therapy. the long half-life of methadone should be taken into account when starting buprenorphine/naloxone therapy. The first dose of buprenorphine/naloxone should only be given after the patient has shown signs of withdrawal and at least 24 hours before the patient’s last methadone dose. In methadone-dependent patients, buprenorphine may produce withdrawal symptoms.
Dosage
Initial treatment (induction)
The recommended initial dose for adults and adolescents over 15 years of age is buprenorphine/naloxone 2mg/0.5mg sublingual tablets, one to two tablets. On the first day, the product buprenorphine/naloxone 2mg/0.5mg sublingual tablet, one to two tablets may be given again, depending on the individual needs of the specific patient.
Close monitoring of the patient at the start of treatment is recommended to ensure proper placement of the sublingual dose and to observe the patient’s response to treatment as a guide to determine an effective titration dose based on clinical effects.
Dose adjustment and maintenance therapy
After the first day of induction therapy, the dose is gradually stabilized over the next few days to an appropriate maintenance dose level based on the clinical effect of the individual patient. Dose titration of buprenorphine is generally in increments or decrements of 2-8 mg, up to a maximum of 24 mg buprenorphine once daily, depending on the patient’s clinical and psychological status reassessed. The maintenance dose is generally in the range of 4/1 mg buprenorphine/naloxone to 24/6 mg buprenorphine/naloxone daily, depending on the individual patient. The recommended target dose for this product is 16/4 mg buprenorphine/naloxone/day once daily.
Less than once-daily dosing
After satisfactory stabilization has been achieved, the frequency of dosing may be reduced to every other day, with each dose being twice the individual daily titrated dose. For example, a patient on 8 mg buprenorphine daily in a stable phase could be given a 16 mg dose every other day with no dosing required during this period. For some patients, the frequency of dosing may be reduced to three times per week (e.g., Monday, Wednesday, and Friday) after satisfactory stabilization has been achieved. The dose on Mondays and Wednesdays should be twice the individual daily titrated dose, and on Fridays the dose should be three times the individual daily titrated dose, during which no dosing is required. However, the dose should not exceed 24 mg on any one day. underdosing may occur in patients with daily titrated doses greater than 8 mg using this method.
Discontinuation of treatment with buprenorphine/nandrolone
After satisfactory stabilization has been achieved, the dose may be tapered to a lower maintenance dose level if the patient agrees; treatment may be discontinued if the condition develops well. This product is available in 2mg/0.5mg and 8mg/2mg sizes to aid titration at reduced doses. Due to the potential for relapse, patients need to be monitored when discontinuing this product.
Special Populations
Geriatric patients
The safety and efficacy of buprenorphine/naloxone sublingual tablets in elderly patients over 65 years of age have not been established. Clinical studies of buprenorphine have not included sufficient numbers of patients 65 years of age and older to determine whether the response in this group of patients differs from that in younger patients. Other reported clinical experiences have not identified differences in response between older and younger patients. In general, caution should be exercised in the selection of doses for older patients. The elderly population, who experience decreased hepatic, renal or cardiac function, have a higher frequency of complications or use other drug therapies, and who can generally be started at lower values of the dose range.
Patients with impaired hepatic function
Baseline liver function tests and documentation of viral hepatitis status are recommended prior to initiation of therapy. There is a risk of accelerated liver injury in patients who are hepatitis virus positive, on combined medications and/or with existing liver dysfunction. Regular monitoring of liver function is recommended (see [Drug Interactions]).
Both active substances of this product, buprenorphine and naloxone, are heavily metabolized by the liver and blood levels of both drugs are relatively high in patients with moderate and severe liver injury. The difference in magnitude of the effects of naloxone and buprenorphine is greater in subjects with severe liver injury than in subjects with moderate liver injury; therefore, the clinical effects of these effects are greater in subjects with severe liver injury than in subjects with moderate liver injury. This product is contraindicated in patients with severe liver injury and is not indicated for use in patients with moderate liver injury.
A low initial dose and careful dose titration are recommended for patients with mild to moderate liver injury.
Patients should be monitored for signs and symptoms associated with withdrawal, intoxication or overdose due to elevated naloxone and/or buprenorphine blood levels. (See [Pharmacokinetic Properties]).
Patients with impaired renal function
No dose adjustment is required for patients with impaired renal function. Caution is advised in patients with severe renal impairment (CLcr <30 mL/min) (see [Special Warnings and Precautions for Use] and [Pharmacokinetic Properties]).
Pediatric population
The safety and efficacy of buprenorphine/naloxone sublingual tablets in children under 15 years of age have not been established.
Mode of Administration
Physicians must caution patients that sublingual administration is the only safe and effective way to administer this drug and that swallowing the tablet will result in decreased bioavailability of the drug. The tablet should be placed under the tongue until it is completely dissolved. Patients should not swallow or drink/eat until the tablet has completely dissolved.
Each dose may consist of different sizes of sublingual tablets of the drug. A single dose may be taken at the same time or may be divided into two parts, with the second part being taken immediately after the first part of the tablet has completed dissolution.
Patients should be shown the correct way to administer the medication.
[Adverse Reactions].
Overview of safety characteristics
In the pivotal clinical study, the most common treatment-related adverse reactions were constipation and common symptoms associated with withdrawal syndrome (e.g., insomnia, headache, nausea, excessive sweating, and pain). Some adverse reactions reported, including seizures, vomiting, diarrhea, and elevated liver function markers were considered serious adverse reactions.
Adverse Reaction List
The following table summarizes the adverse reactions reported in the pivotal clinical study in which 342 of 472 subjects (72.5 %) reported adverse reactions, and also includes adverse reactions reported in post-marketing surveillance.
The frequency of possible adverse reactions described below is defined by the following convention.
Very common (≥ 1/10), common (≥ 1/100 to <1/10), rare (≥ 1/1,000 to <1/100), unknown (not estimable from available data).
Table 1 Treatment-related adverse reactions reported in buprenorphine/naloxone clinical studies and postmarketing surveillance
System Organ Class Very common Common Rare Unknown Infections and Infections Influenza
Infection
Pharyngitis
Rhinitis Urinary tract infections
Vaginal infections Blood and lymphatic system disorders Anemia
Leukocytosis
Decreased white blood cells
Lymphadenopathy
Thrombocytopenia Immune system disorders Hypersensitivity anaphylaxis Metabolic and nutritional disorders Loss of appetite
Hyperglycemia
Hyperlipidemia
Hypoglycemia Mental disorders Insomnia Anxiety
Depression
Decreased libido
Nervousness
Abnormal thinking Abnormal dreams
Agitation
Emotional indifference
Personality disintegration
Drug dependence
Euphoria
Hostile hallucinations Neurological disorders Headache Migraine
Dizziness
Tension hyperactivity
Abnormal sensations
Drowsiness and amnesia
Motor hyperactivity
Epilepsy
Speech disorders
Tremors Hepatic encephalopathy
Fainting eye disease Amblyopia
Tear duct disease Conjunctivitis
Pupillary constriction Ear disorders Vertigo Heart disorders Angina pectoris
Bradycardia
Myocardial infarction
Palpitations
Tachycardia Vascular disease Hypertension
Vasodilatation Hypotension Postural hypotension Respiratory, thoracic and mediastinal disorders Cough Asthma
Dyspnea
Yawning Bronchospasm
Respiratory depression Gastrointestinal disorders Constipation
Nausea Abdominal pain
Diarrhea
Indigestion
Flatulence
Vomiting Mouth ulcers
Tongue discoloration Liver and biliary disease Hepatitis
Acute hepatitis
Jaundice
Hepatic necrosis
Hepatorenal Syndrome Skin and Subcutaneous Tissue Disorders Excessive Sweating Itching
Rashes
Urticaria Acne
Hair loss
Exfoliative dermatitis
Dry skin
Skin lumps angioedema musculoskeletal and connective tissue disorders Back pain
Joint pain
Muscle spasms
Muscle aches and pains Arthritis Kidney and urinary system disorders Abnormal urine proteinuria
Difficulty in urination
Hematuria
Kidney stones
Urinary retention Reproductive and breast disorders Erectile dysfunction Menorrhagia
Ejaculatory disorders
Excessive menstrual flow
Uterine bleeding Systemic diseases and medication site conditions Drug withdrawal syndrome Weakness
Chest pain
chills
fever
malaise and discomfort
pain
Peripheral edema Hypothermia Neonatal drug withdrawal symptoms Screening for liver function abnormalities
Weight loss Elevated creatinine Elevated transaminases Complications of trauma, poisoning, and surgery Injury Heat stroke Adverse events observed from clinical trials conducted in China
The adverse events reported by subjects taking buprenorphine/naloxone sublingual tablets (induction, stabilization and randomization phase trial groups) were consistent with the known safety profile of the product, and no new safety signals were identified.
Description of Selected Adverse Reactions
In the case of intravenous drug abuse, some adverse events were due to the act of abuse itself rather than to the drug: reported symptoms include: local reactions such as infections (abscesses, cellulitis), potentially serious acute hepatitis and other acute infections, pneumonia, and endocarditis.
In some patients with severe drug dependence, initial administration of buprenorphine may produce a drug withdrawal syndrome similar to that caused by co-administration of naloxone.
Reporting of suspected adverse reactions
It is important to report adverse reactions after a drug has been approved for marketing. This allows for continuous monitoring of the benefit/risk balance of the medicinal product. Health care professionals are required to report suspected adverse reactions in accordance with the relevant requirements of laws and regulations.
Adverse reactions observed after opioid use
The following adverse reactions are commonly observed following the initiation or long-term use of opioids
5-hydroxytryptamine syndrome: 5-hydroxytryptamine syndrome is a potentially life-threatening condition that has been reported during the co-administration of opioids with 5-hydroxytryptaminergic drugs.
Adrenal insufficiency: Adrenal insufficiency has been reported following opioid use, often occurring more than a month after drug administration.
Androgen deficiency: Cases of androgen deficiency have been reported following long-term opioid use. (See [Pharmacodynamic and preclinical safety studies].
Contraindications
Buprenorphine/naloxone sublingual tablets should not be used in patients with hypersensitivity to buprenorphine, naloxone, or any of the excipients of this product, as serious adverse reactions, including immediate anaphylactic shock, have been reported (see [Precautions]).
Severe respiratory insufficiency.
Severe hepatic insufficiency.
Acute alcohol intoxication or delirium tremens.
Concomitant administration of opioid antagonists (naltrexone, nalmefene) to treat alcohol or opioid dependence.
【Caution】.
Misuse, abuse and diversion
Similar to other opioids, buprenorphine can be misused or abused in legal or illegal ways. Some of the risks of misuse or abuse include overdose, transmission of blood-borne viral infections, respiratory depression, and liver injury. Buprenorphine, if abused by someone other than the intended patient, poses an additional risk of buprenorphine being used as the primary drug of abuse by a newly dependent person and may be used illicitly due to direct dispersal by the intended patient or theft from improper storage of the drug.
Buprenorphine/naloxone treatment that does not achieve the desired status may cause patients to abuse the drug, leading to overdose or withdrawal from treatment. Patients who do not reach an effective dose of buprenorphine/naloxone may continue to exhibit uncontrolled withdrawal symptoms and self-medicate with opioids, alcohol, or other sedative-hypnotic drugs such as benzodiazepines.
To minimize the risk of misuse, abuse, and diversion, appropriate precautions need to be taken when prescribing and dispensing buprenorphine, such as avoiding prescribing many dispensed medications at the beginning of treatment, following up with patients, and clinically monitoring prescriptions to match patients’ needs.
The combination of buprenorphine and naloxone (this product) is intended to reduce misuse and abuse of buprenorphine. For those patients who are heroin, methadone or other opioid agonist dependent, intravenous and intranasal abuse of this product is reduced compared to buprenorphine because the naloxone in this product promotes withdrawal effects.
Respiratory depression
Some deaths due to respiratory depression have been reported, especially when buprenorphine is used in combination with benzodiazepines or when buprenorphine is not used as prescribed (see [Drug Interactions]). Deaths have also been reported when buprenorphine is used in combination with other sedatives such as alcohol or opioids (see [Drug Interactions]). Potentially fatal respiratory depression may occur if buprenorphine is administered to non-opioid-dependent individuals who are intolerant to opioids.
This product should be used with caution in patients with asthma or impaired respiratory function (e.g., chronic obstructive pulmonary disease, pulmonary heart disease, decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression, or posterior scoliosis (curvature of the spine causing shortness of breath)).
Accidental or intentional administration of buprenorphine/naloxone to children or non-opioid dependent individuals can result in severe and potentially fatal respiratory depression. Patients must be cautioned to store the medication safely, not to tear the blister before taking it, to keep the medication out of the reach of children and other family members, and not to take this medication in the presence of children. In the event of accidental administration or suspected administration of the drug, the emergency room should be contacted immediately.
Central Nervous System Depression
Buprenorphine/naloxone can cause drowsiness, especially when combined with alcohol or other CNS depressants such as analgesics, sedatives, or sleeping pills (see [Drug Interactions]).
Adrenal insufficiency
Cases of adrenal insufficiency have been reported following opioid use, often occurring more than a month after administration. Clinical manifestations of adrenal insufficiency may include nonspecific signs and symptoms, such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension. If adrenal insufficiency is suspected, it should be confirmed by diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Discontinue the patient’s opioid therapy to facilitate restoration of their adrenal function while continuing corticosteroid therapy until adrenal function is restored. Other opioids may be tried, as some cases have been reported where the use of a different opioid may not trigger adrenal insufficiency. The information available at this time does not establish that any particular opioid is more likely to cause adrenal insufficiency.
Dependence
Buprenorphine is a partial agonist of the mu-opioid receptor and produces opioid dependence with chronic dosing. Experiments in animals as well as clinical experience suggest that buprenorphine may produce dependence, but to a lesser extent than full agonists.
Abrupt discontinuation of treatment is not recommended because of its potential to cause delayed withdrawal syndrome episodes.
Neonatal opioid withdrawal syndrome (NOWS) is a predictable and treatable outcome of long-term opioid use during pregnancy (see [Medications for Pregnant and Lactating Women]).
Hepatitis, Hepatic Events
Acute liver injury has been reported in opioid-dependent patients in clinical trials and post-marketing adverse reaction reports. The abnormalities range from a transient asymptomatic elevation in liver transaminases to case reports of liver failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy, and death. In many cases, patients with pre-existing mitochondrial impairment (genetic disorders, liver enzyme abnormalities, viral infections such as hepatitis B and C, alcohol abuse, anorexia, and combined use of other potentially hepatotoxic medications) are a contributing factor, as is the continued injection of the drug. These potential factors must be considered before prescribing buprenorphine/naloxone and during treatment. When a hepatic event is suspected, further biological and etiologic evaluation is required.
Based on these findings, medication discontinuation needs to be undertaken with caution to avoid withdrawal symptoms as well as to prevent patients from returning to illicit drug use. If treatment is continued, liver function should be closely monitored.
Allergic reactions
Cases of hypersensitivity to drugs containing buprenorphine/naloxone components have been reported in both clinical trials and post-marketing experience. Cases of bronchospasm, angioedema, and anaphylaxis have been reported. The most common signs and symptoms include rash, urticaria, and pruritus. Therefore, the use of buprenorphine/naloxone sublingual tablets should be contraindicated in patients with a history of buprenorphine/naloxone allergy.
Promotion of opioid withdrawal syndrome
When initiating treatment with buprenorphine/naloxone, physicians must be aware of the partial agonist profile of buprenorphine and its ability to precipitate withdrawal in opioid-dependent patients, particularly when the drug is taken within six hours of the last use of heroin or other short-acting opioids, or within 24 hours of the last use of methadone. Because withdrawal symptoms have been reported when switching from buprenorphine or from methadone to buprenorphine/naloxone, patients should be monitored closely during the switch. To avoid precipitating withdrawal, patients should have demonstrated objectively significant withdrawal symptoms prior to buprenorphine/naloxone induction (see [DOSAGE]).
Because of the presence of naloxone, buprenorphine/naloxone sublingual tablets tend to promote significant and severe withdrawal symptoms when administered intravenously to patients dependent on full opioid agonists such as heroin, morphine, or methadone.
Withdrawal symptoms may also be associated with failure to achieve the desired therapeutic dose.
Use in opioid-intolerant patients
There have been reports of death in opioid intolerant patients taking 2mg doses of buprenorphine sublingual tablets as an analgesic. This product is not suitable as an analgesic.
Impaired hepatic function
A post-marketing study evaluated the pharmacokinetic effects of impaired hepatic function on buprenorphine and naloxone. Both buprenorphine and naloxone are heavily metabolized, so blood levels of both drugs are elevated in patients with moderate and severe hepatic impairment and may require dose adjustment. Blood concentrations of naloxone and buprenorphine are more elevated in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, so the clinical effects may be greater in patients with severe hepatic impairment than in patients with moderate hepatic impairment. Buprenorphine/naloxone sublingual tablet products are contraindicated in patients with severe hepatic impairment and may not be appropriate in patients with moderate hepatic impairment.
Patients should be monitored for signs and symptoms of precipitated withdrawal, toxic toxicity or overdose due to elevated naloxone and/or buprenorphine blood levels. Lower initial doses and more careful dose adjustments are recommended in patients with mild to moderate hepatic impairment. (See [Pharmacokinetics]).
Impaired Renal Function
Since renal elimination accounts for 30% of buprenorphine elimination, renal elimination may be prolonged in patients with impaired renal function. Metabolites of buprenorphine can accumulate in patients with renal failure. Caution is recommended in patients with severe renal impairment (CLcr <30mL/min) (see [Dosage] and [Pharmacokinetics]).
Adolescent Use (15-<18 years)
Due to the lack of data for adolescents in the 15-<18 age group, children should be monitored more closely during treatment.
Dosage for Athletes
Use with caution in athletes.
Neonatal Opioid Withdrawal Syndrome (NOWS)
Neonatal opioid withdrawal syndrome (NOWS) is a predictable and treatable outcome of prolonged opioid use during pregnancy, whether medically licensed or prohibited.NOWS presents with restlessness, hyperactivity and sleep abnormalities, loud crying, tremors, vomiting, diarrhea, and/or abnormal weight gain.The duration and severity of withdrawal symptoms vary with the individual and should be closely monitored and managed appropriately. Unlike opioid withdrawal syndrome in adults, failure to recognize and treat NOWS in neonates can be life-threatening. Health care professionals should observe newborns for signs of NOWS and manage accordingly (see [Medication for Pregnant and Lactating Women]).
Inform pregnant women receiving this product for opioid addiction about the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment can be provided (see [Medications for Pregnant and Lactating Women]). Untreated opioid addiction often leads to continued or renewed illicit opioid use and is associated with adverse pregnancy outcomes, which must be weighed against the pros and cons. Therefore, prescribers should discuss the importance and benefits of opioid addiction management throughout pregnancy.
CYP 3A Inhibitors
CYP3A4 enzyme inhibiting drugs may increase buprenorphine blood levels. Therefore, a reduction in the dose of buprenorphine/naloxone may be necessary. Caution should be exercised when titrating buprenorphine/naloxone sublingual tablets to patients already treated with CYP3A4 inhibitors
as a dose reduction may be sufficient for these patients (see [Pharmacokinetics]).
Effects on the ability to drive and use machinery
When buprenorphine/naloxone sublingual tablets are used in opioid-dependent patients, this product may cause mild to moderate effects on the patient’s ability to drive and operate machinery. This product may cause drowsiness, dizziness, or impaired thinking ability, especially during treatment induction and dose adjustment. Effects may be more pronounced if alcohol or CNS depressants are used in combination (see [Pharmacokinetics]).
Patients are warned to exercise caution when driving or operating dangerous machinery because buprenorphine/naloxone sublingual may impair their ability to participate in such activities unless they can be reasonably certain that treatment with buprenorphine/naloxone sublingual will not adversely affect his or her ability to participate in such activities.
General Warnings
Buprenorphine/naloxone sublingual tablets contain lactose. Patients with a rare genetic problem of galactose intolerance should not take this medication (see [Ingredients]).
General Opioid Medication Related Warnings
Opioids may produce postural hypotension in ambulatory patients.
Opioids may elevate cerebrospinal fluid pressure, which may lead to seizures; therefore, opioids should be used with caution in patients with craniocerebral injury, patients with intracranial occupying lesions, and patients with elevated cerebrospinal fluid pressure or a history of seizures.
Opioids should be used with caution in patients with hypotension, prostatic hypertrophy, or urethral stricture.
Opioids can cause pupillary constriction, alter the level of consciousness, or alter the perception of pain when it is a symptom of a disease, which may interfere with the evaluation of the patient or impede the diagnosis or clinical course of concomitant disease.
Opioids should be used with caution in patients with mucinous edema, hypothyroidism, or impaired adrenocortical function (e.g., Addison’s disease).
Opioids have been shown to elevate intra-biliary pressure and should therefore be used with caution in patients with biliary tract dysfunction.
Similar to other opioids, buprenorphine can affect the diagnosis and clinical course of patients with acute abdominal pain.
Opioids should be used with caution in the elderly or frail.
Based on experience with morphine, the combination of a monoamine oxidase inhibitor (MAOI) may amplify opioid effects (see [Drug Interactions]).
Pregnant women and nursing mothers
Pregnancy
There are insufficient data on the use of this product in pregnant women. The potential risk to humans is uncertain (see [Pharmacology and Toxicology]).
Buprenorphine/naloxone sublingual tablets should be used during pregnancy under the evaluation of a physician.
Buprenorphine/Naloxone Sublingual Tablets should be used only when the potential benefit to the fetus outweighs the potential risk.
Short-term administration of buprenorphine by the mother at the end of pregnancy may result in respiratory depression in the newborn. Prolonged use of buprenorphine by mothers in the late trimester may result in the development of withdrawal syndrome (e.g., hyperactivity, neonatal tremor, neonatal agitation, myoclonus, or convulsions) in the newborn. The syndrome typically appears within a few hours to a few days after birth.
Because of the long half-life of buprenorphine, neonatal monitoring for several days at the end of pregnancy should be considered to prevent the risk of respiratory depression or withdrawal syndrome in the newborn.
Labor or delivery
As with all opioids, the use of buprenorphine prior to delivery may result in respiratory depression in the neonate. Monitor the newborn closely for signs of respiratory depression. An opioid receptor antagonist such as naloxone should be prepared to reverse opioid-induced respiratory depression in the neonate.
Breastfeeding
Based on 2 studies in 13 breastfeeding women, levels of buprenorphine and its metabolite, norbuprenorphine, were low in human milk and infant urine, and the available data did not indicate adverse effects in nursing infants. There are no data on the compounded drug buprenorphine/naloxone sublingual tablets in breastfeeding, but oral absorption of naloxone is minimal. Caution should be exercised when administering buprenorphine/naloxone sublingual tablets to nursing females. The developmental and health benefits of breastfeeding should be considered in conjunction with the mother’s clinical need for buprenorphine/naloxone sublingual tablets and the potential adverse effects of the drug or the mother’s underlying medical condition on the nursing child. When administered to nursing women, young children should be monitored for signs of drowsiness and dyspnea.
Fertility
Animal studies have shown that the use of high doses (based on AUC, buprenorphine systemic exposure is greater than 2.4 times the maximum recommended human dose of 24 mg) of buprenorphine can lead to decreased fertility in females. Long-term opioid use may lead to decreased fertility in females as well as males. It is not clear whether the effects on fertility are reversible. (See [Adverse Reactions] and [Pharmacology and Toxicology]).
Pediatric use]
The safety and efficacy of buprenorphine/naloxone in children under 15 years of age is uncertain. No relevant data are available.
Geriatric use]
Dosage selection should be cautious in elderly patients in general, usually starting at the low end of the dose range (see [Dosage]).
Drug Interactions]
Buprenorphine/Naloxone Sublingual Tablets should be used with caution when combined with the following drugs.
Drugs containing alcohol: Because alcohol enhances the sedative effect of buprenorphine/naloxone sublingual tablets. Buprenorphine/naloxone sublingual tablets should not be combined with alcohol-containing beverages.
Benzodiazepines: Combination may result in death due to central respiratory depression. There have been many post-marketing reports of coma and death from the combination of buprenorphine and benzodiazepines. Many of these reports (not all) were self-injections of buprenorphine by mistake. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine alters the usual ceiling effect on buprenorphine-induced respiratory depression, making buprenorphine similar to the respiratory effects of those full opioid receptor agonists. Therefore, drug doses must be limited as well as drug combinations avoided to prevent the risk of misuse. Patients should be warned that self-administration of over-the-counter benzodiazepines while taking this product is extremely dangerous, and that benzodiazepines and this product should be used in combination only with caution and under medical supervision.
Other CNS depressants, other opioids (e.g., methadone, analgesics, cough suppressants), certain antidepressants, sedatives, H1 receptor antagonists, barbiturates, anxiolytics (non-benzodiazepines), antipsychotics, colistin, and related substances: the combination of these may enhance CNS depression due to additive effects between drugs and may result in hypotension, respiratory depression increased risk of hypotension, respiratory depression, excessive sedation, coma, and death. Decreased levels of alertness may cause driving and mechanical handling hazards. Further, when patients treated with buprenorphine/naloxone take opioid receptor full agonists, it may be difficult to achieve adequate analgesia. Therefore there is a risk of overdose when combined with a full opioid agonist, especially when attempting to overcome the partial agonist effect of buprenorphine, or when the blood levels of buprenorphine are reduced. The combination of these drugs may be reserved for patients with inadequate alternative treatment regimens. Keep the dose and duration to the minimum required by the patient. Closely follow patients for signs of respiratory depression and sedation.
Naltrexone and nalmefene are opioid receptor antagonists that block the pharmacologic effects of buprenorphine. Combination of buprenorphine/naloxone is contraindicated in the use of buprenorphine/naloxone as it may promote sudden onset of prolonged and intense opioid withdrawal symptoms.
Cytochrome P-450 3A4 (CYP3A4) inhibitors and inducers: Buprenorphine is primarily metabolized to norbuprenorphine by the cytochrome CYP3A4; therefore, potential interactions may occur when buprenorphine/naloxone sublingual tablets are administered concomitantly with drugs that affect CYP3A4 activity.
Coadministration of buprenorphine/naloxone sublingual tablets with CYP3A4 inhibitors (e.g., azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors) can increase plasma concentrations of buprenorphine, resulting in increased or prolonged opioid effects, especially when a stable dose is obtained followed by the addition of an inhibitor. If a combination is required, consider reducing the dose of buprenorphine/naloxone sublingual tablets until a stable drug effect is obtained. Monitor patients frequently for respiratory depression and sedation. After discontinuation of CYP3A4 inhibitors, buprenorphine plasma concentrations will decrease as the effects of the inhibitor diminish, which may lead to decreased opioid efficacy or allow for withdrawal syndrome in patients who have developed physical dependence on buprenorphine. If the CYP3A4 inhibitor is discontinued, consider increasing the dose of buprenorphine/naloxone sublingual tablets until a stable drug effect is obtained. Monitor patients for opioid withdrawal symptoms in real time.
The combination of buprenorphine and CYP3A4 inducers decreases the plasma concentration of buprenorphine, which may result in a decrease in the efficacy of the drug or make withdrawal syndrome flare up in patients already physically dependent on buprenorphine. After discontinuation of CYP3A4 inducers, buprenorphine plasma concentrations will increase as the effects of the inducer diminish, which may lead to increased therapeutic effects and increased adverse effects, or lead to prolonged duration of both, and may even lead to severe respiratory depression. If a combination is necessary, consider increasing the dose of buprenorphine/naloxone sublingual tablets until a stable drug effect is obtained. Monitor the patient for opioid withdrawal symptoms. If CYP3A4 inducers (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, rifampin) are discontinued, consider decreasing the dose of buprenorphine/naloxone sublingual tablets while monitoring the patient for signs of respiratory depression (see [Pharmacokinetics]).
Antiretrovirals: The interaction of CYP3A4 with buprenorphine has been evaluated using 3 classes of antiretroviral drugs. Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway and therefore no interaction with buprenorphine is expected. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are primarily metabolized via CYP3A4. Efavirenz, nevirapine and etravirine are known CYP3A inducers, while delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. It is recommended that patients on long-term buprenorphine therapy who add NNRTIs to their own regimen should monitor their dose. Studies have shown that some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitor activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little to no pharmacodynamic effect on buprenorphine and no significant pharmacodynamic effect. Other PIs with CYP3A4 inhibitor activity (atazanavir and atazanavir/ritonavir) resulted in increased levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Opioid overdose symptoms in patients receiving buprenorphine and atazanavir with or without ritonavir were identified in post-marketing reports. Testing of patients receiving buprenorphine and atazanavir plus or minus ritonavir is recommended and buprenorphine may require dose reduction.
Based on experience with morphine, the combination of a monoamine oxidase inhibitor (MAOI) may amplify opioid effects. interactions between MAOIs and opioids may manifest as 5-hydroxytryptamine syndrome or opioid toxicity (e.g., respiratory depression, coma). Buprenorphine/naloxone therapy is not recommended for patients on MAOI therapy or within 14 days of discontinuation of this therapy.
5-hydroxytryptaminergic drugs: The combination of opioids with other drugs that affect the 5-hydroxytryptaminergic neurotransmitter system can cause 5-hydroxytryptamine syndrome. If a combination is necessary, the patient should be closely monitored, especially during treatment initiation and dose adjustment. If 5-hydroxytryptamine syndrome is suspected, buprenorphine treatment should be discontinued.
Muscle relaxants: Buprenorphine may increase the neuromuscular blocking effect of skeletal muscle relaxants and cause greater respiratory depression. Monitor patients receiving muscle relaxants and buprenorphine for signs of respiratory depression (which may be more severe than expected with non-combination medications) and reduce the dose of buprenorphine/naloxone sublingual tablets and/or muscle relaxants as necessary.
Diuretics: Opioids are capable of attenuating the therapeutic effects of diuretics by inducing the release of antidiuretic hormones. Monitor the patient for signs of decreased diuresis and/or changes in blood pressure and increase the dose of this diuretic as needed.
Anticholinergics: Combination with anticholinergics may increase the risk of urinary retention and/or severe constipation, which in turn may cause paralytic bowel obstruction. When patients are treated with the combination of buprenorphine and anticholinergic drugs, they should be monitored in real time for signs of urinary retention or decreased gastric motility.
[Drug overdose].
Symptoms
In the case of overdose, respiratory depression due to central nervous system depression is the main symptom requiring intervention, and respiratory depression may lead to respiratory arrest and death. Manifestations of overdose also include drowsiness, amblyopia, pupillary constriction, decreased blood pressure, nausea, vomiting and/or speech disturbances.
Treatment
General supportive measures should be given, including close monitoring of the patient’s respiratory and cardiac status. Respiratory depression should be treated symptomatically and given standard intensive care measures. Airway patency, as well as assisted or controlled ventilation, must be ensured. Patients should be transferred to a fully resuscitated environment with full resuscitation equipment.
If the patient vomits, care must be taken to prevent inadvertent aspiration of vomitus.
An opioid receptor antagonist (i.e., naloxone) is recommended, although it has the potential to only modestly reverse buprenorphine-induced respiratory symptoms compared to its effect on full opioid receptor agonists.
If naloxone is used, the longer duration of action of buprenorphine should be taken into account when determining the cycle of medical monitoring and treatment cycles required to reverse the effects of drug overdose. The ability of naloxone to clear more rapidly than buprenorphine in the body can lead to a recurrence of previously controlled buprenorphine overdose symptoms, so continuous infusions may be required, and if infusions are not available, naloxone administration may be repeated. The initial naloxone dose may be as high as 2 mg and should be repeated every 2-3 minutes until a satisfactory response is obtained, but this initial dose should not exceed a total of 10 mg. The rate of intravenous infusion should be adjusted according to the patient’s response.
Clinical Trials]
Clinical data on the safety and efficacy of buprenorphine/naloxone sublingual tablets were obtained from studies of buprenorphine sublingual tablet dosage forms, with or without naloxone, and from studies of sublingual administration of the more bioavailable buprenorphine ethanol solution.
Buprenorphine/naloxone sublingual tablets were studied in 575 patients, buprenorphine (without naloxone) sublingual tablets in 1834 patients, and buprenorphine ethanol sublingual solution in 2470 patients. In total, 1270 women received buprenorphine in these clinical trials. Dosing recommendations were based on data from 1 trial of tablets and 2 trials of buprenorphine ethanol sublingual solution. All trials used buprenorphine in combination with psychosocial counseling as part of a complete addiction treatment program. No clinical studies evaluated the effectiveness of buprenorphine as the sole treatment.
Efficacy and safety data for buprenorphine/naloxone were primarily from a 1-year clinical trial that included a 4-week randomized, double-blind comparative study of buprenorphine/naloxone, buprenorphine versus placebo tablets, and a subsequent 48-week safety study of buprenorphine/naloxone. In this study, 326 heroin addicts were randomized to receive buprenorphine/naloxone 16 mg/4 mg day, buprenorphine 16 mg/day, or placebo tablets for treatment. Patients randomized to receive either positive drug received 8 mg of buprenorphine on day 1 and 16 mg (two 8 mg tablets) of buprenorphine on day 2. On day 3, patients randomized to receive buprenorphine/naloxone sublingual tablets were switched to the compounded formulation. Subjects randomized to the placebo group received one placebo sublingual tablet on day 1 and two placebo sublingual tablets daily for four weeks thereafter. Subjects were observed at the clinic (Monday through Friday) for medication administration and effectiveness assessment. Take-home doses of medication were provided at the end of the week. As instructed, subjects were required to hold the medication under the tongue for approximately 5-10 minutes until it was completely dissolved. Subjects received counseling on HIV infection and up to 1 hour of personal counseling per week. The primary comparison of the study was to evaluate the effectiveness of buprenorphine sublingual tablets alone and buprenorphine/naloxone sublingual tablets compared to placebo. A significantly higher proportion of urine samples from buprenorphine/naloxone sublingual tablets three times per week were negative for non-study opioids than placebo (p < 0.0001), and a significantly higher proportion of urine samples from buprenorphine sublingual tablets three times per week were negative for non-study opioids than placebo (p < 0.0001).
In a double-blind, double-model, parallel-controlled study comparing buprenorphine ethanol solution with a full agonist positive control drug, 162 subjects were randomized to receive buprenorphine ethanol sublingual solution 8 mg/day (a dose approximately equivalent to buprenorphine/naloxone 12 mg/3 mg day), 2 low-dose positive control drugs, with one active control drug at a lower dose equivalent to placebo. The study included a 3-10 day induction period, a 16 week maintenance period with a 7 week discontinuation period. The buprenorphine group was titrated to the maintenance dose on day 3; the dose of the positive control drug was titrated gradually.
Maintenance dosing continued until week 17, after which the drug was tapered at a rate of 20%30% per week during weeks 18 – 24, with the final 2 weeks being placebo dosing. Subjects received weekly individual and/or group counseling.
The results of treatment maintenance rates versus 3 negative weekly urine tests for non-study opioids suggest that buprenorphine is more effective than low-dose positive controls in ensuring continued treatment versus reduced opioid use in heroin-addicted patients. The effectiveness of buprenorphine 8 mg/day was similar to that of a moderate dose positive control drug, but equivalence has not been demonstrated.
In a dose-control, double-blind, parallel-group, 16-week study, 731 subjects were randomized to receive one of four doses of buprenorphine ethanol sublingual solution: 1 mg, 4 mg, 8 mg, and 16 mg. Buprenorphine ethanol sublingual solution was titrated to a maintenance dose over 1-4 days and continued for 16 weeks of treatment. Subjects received at least 1 AIDS education session, and other counseling ranged from 1 hour per month to 1 hour per week, depending on the study center.
The 3 highest trial doses were superior to the 1 mg dose based on treatment retention and the proportion of urine samples becoming non-study opioid negative three times a week. Thus, this study shows a range of potentially effective buprenorphine doses. 1 mg doses of buprenorphine ethanol sublingual solution were considered slightly lower than 2 mg tablet doses. The other doses in the study were equivalent to approximately 6 mg – approximately 24 mg tablet dose.
A randomized, double-blind and placebo-controlled, phase III clinical trial examining buprenorphine/naloxone sublingual tablets was successfully completed in China. A total of 442 opioid-addicted subjects were screened and 260 subjects were randomized and enrolled, with 130 subjects in the buprenorphine/naloxone sublingual group and 130 subjects in the placebo group. The induction period was 3 – 5 days. The stabilization period lasted 7 – 21 days; the randomization/treatment period lasted 6 weeks. Treatment failure occurred in 82 (63.1%) and 119 (91.5%) cases in the trial and control groups, respectively. Thus, treatment failure was significantly less in the trial group than in the control group (p < 0.0001). The median duration of continuous treatment was 32 days (95% CI, 26-38) and 6 days (95% CI, 5-8) in the trial and control groups, respectively, with a Cox hazard ratio of 0.28 (95% CI, 0.21-0.38; P < 0.0001).
[Pharmacological Toxicology].
Pharmacological effects
Buprenorphine hydrochloride naloxone sublingual tablets contain two main ingredients, buprenorphine and naloxone. Buprenorphine is a partial agonist of the μ-opioid receptor and an antagonist of the κ-opioid receptor; naloxone is a strong antagonist of the μ-opioid receptor, and non-intestinal administration can produce signs and symptoms of opioid withdrawal in opioid agonist-dependent patients.
Toxicological studies
Genotoxicity
The Ames test, in vitro human lymphocyte genetic assay and rat micronucleus assay (intravenous administration) for the 4:1 combination of buprenorphine hydrochloride and naloxone hydrochloride were negative.
A series of studies on the interaction of buprenorphine with genes, chromosomes and DNA were conducted in prokaryotic and eukaryotic cell systems. Negative results were obtained in yeast (Saccharomyces cerevisiae) for teratogenicity of genetic recombination, gene transformation or forward mutation; in Bacillus subtilis “rec” test; in CHO cells, Chinese hamster bone marrow cells and spermatogonia for chromosome breakage; and in mouse lymphoma L5178Y test. The Green-Tweets (Escherichia coli) survival test was positive, the DNA synthesis inhibition test (DSI test) with mouse testicular tissue doped with [3H]thymidine nucleoside in vivo and in vitro was positive, and the non-coding DNA synthesis test (UDS test) with mouse testicular tissue was positive. .
Reproductive toxicity
Reduced female fertility was observed in rats given buprenorphine at 500 ppm and above (47 mg/kg/day and above; 28 times the recommended human dose of 16 mg in mg/m2 ) by adulteration. No adverse effects on fertility were observed in rats given buprenorphine at doses of 100 ppm (equivalent to 10 mg/kg/day and above; 6 times the recommended human dose of 16 mg in mg/m2) by adulteration.
The effects on embryo-fetal development were examined in rats and rabbits given a mixture of buprenorphine and naloxone by oral (1:1) or intramuscular injection (3:2). No teratogenic effects were observed in rats and rabbits given buprenorphine orally at a maximum dose of 250 mg/kg/day and 40 mg/kg/day (150 and 50 times the recommended daily sublingual dose of 16 mg in humans, respectively, on a mg/m2 basis). No definite drug-related teratogenic effects were observed in rats and rabbits administered intramuscular buprenorphine 30 mg/kg/day (20 and 35 times the recommended daily sublingual dose of 16 mg in humans, based on mg/m2, respectively). One case of headless fetus in the low-dose group and two cases of umbilical protrusion in the same litter of rabbit embryos in the medium-dose group were observed, while no abnormality was observed in the high-dose group. Dose-related post-implantation loss was seen in rats given buprenorphine 10 mg/kg/day and above (at mg/m2, 6 times the recommended daily sublingual dose of 16 mg in humans), and increased post-implantation loss was seen in rabbits given buprenorphine 40 mg/kg/day orally. Increased post-arrival loss was seen in rats and rabbits after intramuscular administration of buprenorphine 30 mg/kg/day, suggesting a decrease in live embryos and increased resorption.
Buprenorphine 5 mg/kg/day was administered intramuscularly or subcutaneously to rats and rabbits (3 and 6 times the human recommended daily sublingual dose of 16 mg, respectively, based on mg/m2), buprenorphine 0.8 mg/kg/day was administered intravenously to rats and rabbits (0.5 and 1 times the human recommended daily sublingual dose of 16 mg, respectively, based on mg/m2), and buprenorphine 160 mg/kg/day was administered orally to rats 160 mg/kg/day (95 times the recommended daily sublingual dose of 16 mg in mg/m2) in rats and 25 mg/kg/day (30 times the recommended daily sublingual dose of 16 mg in mg/m2) in rabbits, and no teratogenic effects were observed. Skeletal abnormalities were increased in rats given intravenous buprenorphine at 1 mg/kg/day and above (0.6 times the recommended daily sublingual dose of 16 mg at mg/m2), but not in rats given orally at doses up to 160 mg/kg/day. No statistically significant data were found for skeletal abnormalities in rabbits given buprenorphine 5 mg/kg/day intramuscularly (6 times the recommended daily sublingual dose of 16 mg on a mg/m2 basis) or 1 mg/kg/day or more orally (equivalent to the recommended daily sublingual dose of 16 mg on a mg/m2 basis).
Pre-arrival loss was seen in rabbits given buprenorphine orally at 1 mg/kg/day and above, and post-arrival loss was seen in rabbits given intravenously at 0.2 mg/kg/day and above (0.3 times the human recommended daily sublingual dose of 16 mg on a mg/m2 basis). An increased rate of obstructed labor was seen in pregnant rats given intramuscular buprenorphine at 5 mg/kg/day and above (3 times the recommended daily sublingual dose of 16 mg in humans based on mg/m2).
In rats, buprenorphine was given orally at 0.8 mg/kg/day and above (0.5 times the human recommended daily sublingual dose of 16 mg at mg/m2), intramuscularly at 0.5 mg/kg/day and above (0.3 times the human recommended daily sublingual dose of 16 mg at mg/m2), subcutaneously at 0.1 mg/kg/day and above (0.1 times the human recommended daily sublingual dose of 16 mg at mg/m2), and subcutaneously at 0.1 mg/kg/day and above (0.1 times the human recommended daily sublingual dose of 16 mg at mg/m2). m2 , 0.06 times the recommended human sublingual daily dose of 16 mg), fertility and pre- and postnatal developmental studies showed increased neonatal mortality. It was found that the reduction in pup viability and lactation indicators may be related to reduced maternal milk production.
In female rats given orally buprenorphine 80 mg/kg/day and above (50 times the recommended human sublingual daily dose of 16 mg at mg/m2), a delay in the righting reflex and startle response was seen in pups.
Carcinogenicity
In a carcinogenicity test in Alderley Park rats given buprenorphine/naloxone (4:1 base ratio) by adulteration, buprenorphine/naloxone was administered at doses of 7, 31, and 123 mg/kg/day (4, 18, and 44 times the recommended human dose of buprenorphine/naloxone 16/4 mg based on AUC comparisons) for 104 weeks. The results showed an increased incidence of benign testicular mesenchymal stromal cell tumors in all dose groups.
The carcinogenicity of buprenorphine was studied in SD rats and CD-1 mice. Doses of 0.6, 5.5, and 56 mg/kg/day (0.4, 3, and 35 times the recommended human dose of 16 mg in mg/m2) were administered to rats for 27 months. Consistent with the results of the buprenorphine/naloxone rat carcinogenicity assay, a dose-related increase in testicular mesenchymal stromal cell tumors was seen. In an 86-week adulterated carcinogenicity study in CD-1 mice, buprenorphine was not found to be carcinogenic at doses up to 100 mg/kg/day (30 times the recommended human dose of 16 mg in mg/m2).
Pharmacokinetics
Absorption and distribution
Buprenorphine, when administered orally, is metabolized in the small intestine and liver via N-desalkylation with glucosinolate conjugation in the first pass. Therefore, it is not suitable to use this drug by oral route.
Peak plasma concentrations are reached after 90 minutes of sublingual administration. Plasma concentrations of buprenorphine increased with increasing sublingual doses of buprenorphine/naloxone (Table 2). Buprenorphine Cmax and AUC also increased with increasing dose (4-16 mg), but the increase was less than the increase in dose.
Table 2. Pharmacokinetic parameters of buprenorphine, norbuprenorphine and naloxone after buprenorphine/naloxone sublingual tablet administration (mean ± SD) PK parameters Dose of buprenorphine/naloxone sublingual tablet (mg) 2/0.5 8/2 Buprenorphine Cmax (ng/mL) 0.780 ± 0.323 2.58 ± 1.10 Tmax# (hr) 1.50 ( 0.75-3.00) 1.50 (0.50-3.03) AUCinf (ng.hr/mL) 7.651 ± 2.650 25.31 ± 9.500 t1/2 (hr) 30.75 ± 15.04 31.94 ± 15.27 norbuprenorphine Cmax (ng/mL) 0.293 ± 0.129 1.35 ± 0.977 Tmax# (hr) 1.25 (0.50-8.00) 1.25 (0.75-12.00) AUCinf (ng.hr/mL) 13.59 ± 4.887 52.84 ± 31.15 t1/2 (hr) 45.84 ± 15.85 44.76 ± 28.74 Naloxone Cmax (pg/mL) 51.3 ± 21.1 135 ± 57.3 Tmax# (hr) 0.75 (0.30-1.50) 0.75 (0.50-1.25) AUCinf (pg ∙ hr/mL) 124.2 ± 52.49 374.6 ± 132.8 t1/2 (hr) 5.15 ± 5.28 7.65 ± 3.99 #: Tmax expressed as Median value (min-max)
Buprenorphine enters the rapid distribution phase after absorption (distribution half-life of 2-5 hours).
The protein binding of buprenorphine is approximately 96% and is primarily bound to alpha and beta globulins.
After intravenous administration, naloxone is rapidly distributed (distribution half-life of about 4 minutes). After oral administration, naloxone is not readily detectable in plasma; after sublingual administration of buprenorphine/naloxone sublingual tablets, the blood concentration of naloxone is very low and decreases rapidly. Naloxone does not affect the pharmacokinetics of buprenorphine after sublingual administration of buprenorphine/naloxone sublingual tablets.
The protein binding of naloxone is approximately 45% and is primarily bound to albumin.
Biotransformation and elimination
Buprenorphine undergoes N-dealkylation to form norbuprenorphine, which then undergoes glucuronidation. the N-dealkylation pathway is primarily mediated by CYP3A4. Norbuprenorphine, the main metabolite, can continue to undergo glucuronidation. Desmethylbuprenorphine has been found to bind opioid receptors in vitro; however, its opioid-like activity has not been studied in the clinic.
Substance balance studies of buprenorphine have shown complete recovery of radiolabel from urine (30%) and stool (69%) 11 days after continuous intravenous infusion. Almost all of the radioactive dose was from buprenorphine, norbuprenorphine, and two unknown buprenorphine metabolites. In the urine, buprenorphine and norbuprenorphine were mostly bound (buprenorphine, 1% free 9.4% bound; norbuprenorphine, 2.7% free 11% bound). In the feces, almost all buprenorphine and norbuprenorphine were free (buprenorphine, 33% free 5% bound; norbuprenorphine, 21% free 2% bound). Based on the studies reported in Table 2, the mean plasma terminal half-life of buprenorphine ranged from 31 – 32 hours.
Naloxone undergoes direct glucuronidation to form naloxone-3-glucosinolate, as well as N-dealkylation, and reduction of the 6-oxygen group.
The mean plasma terminal half-life of naloxone is between 2 – 12 hours.
Drug Interactions
CYP3A4 Inhibitors and Inducers: Buprenorphine/naloxone sublingual tablets administered concomitantly with CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), and HIV protease inhibitors should be monitored in subjects, and one or both may require dose reduction. Interactions of buprenorphine with all CYP3A4-inducing agents have not been studied; therefore, it is recommended that patients treated with buprenorphine/naloxone sublingual tablets should be monitored if administered concomitantly with CYP3A4-inducing agents (e.g., phenobarbital, carbamazepine, phenytoin, rifampin) (see [Drug Interactions]).
In an in vitro study using human liver microsomes, buprenorphine was found to be a CYP2D6 and CYP3A4 inhibitor, and its major metabolite, norbuprenorphine, was a moderate CYP2D6 inhibitor. However, the plasma concentrations of buprenorphine and norbuprenorphine are relatively low at therapeutic doses and no significant drug-drug interaction problems are expected.
Special Populations
Geriatric patients
No pharmacokinetic information is available for elderly patients.
Impaired renal function
Renal excretion contributes relatively little (approximately 30%) to the overall clearance of buprenorphine/naloxone. No dose adjustment based on renal function is required, but caution is recommended when administering to subjects with severe renal impairment (creatinine clearance <30 mL/min).
Impaired liver function
The effect of impaired hepatic function on the pharmacokinetics of buprenorphine and naloxone was evaluated in a post-marketing study. The distribution of buprenorphine and naloxone was measured in subjects with varying degrees of hepatic impairment according to Child-Pugh criteria who received buprenorphine/naloxone 2.0 mg/0.5 mg sublingual tablets. The distribution of buprenorphine and naloxone in patients with impaired liver function was compared with that in subjects with normal liver function.
Changes in mean Cmax, AUC0-last, and half-life values of buprenorphine and naloxone were not clinically significant in subjects with mild hepatic impairment. No dose adjustment was required in patients with mild hepatic impairment.
In subjects with moderate and severe hepatic impairment, mean Cmax, AUC0-last, and half-life values were elevated for both buprenorphine and naloxone; the effect was more pronounced for naloxone than for buprenorphine (Table 3).
Table 3. altered pharmacokinetic parameters in subjects with moderate and severe hepatic impairment Pharmacokinetic parameters of hepatic impairment elevated with buprenorphine compared to healthy subjects Elevated with naloxone compared to healthy subjects Moderate Cmax8% 170% AUC0-last64% 218% Half-life 35% 165% Severe Cmax72% 1030% AUC0- last181% 1302% Half-life57% 122%
The difference in the magnitude of effects to naloxone and buprenorphine was greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment; therefore, the clinical impact of these effects may be greater in patients with severe hepatic impairment than in patients with moderate hepatic impairment.
Buprenorphine/naloxone products are contraindicated in patients with severe hepatic impairment and may not be appropriate in patients with moderate hepatic impairment (see [Precautions]).
Hepatitis C Infection
No clinically meaningful changes in mean Cmax, AUC0-last, and half-life values of buprenorphine and naloxone were observed in subjects with HCV infection without manifestations of hepatic impairment compared to healthy subjects without HCV infection. no dose adjustment is required in patients with HCV infection.
Pharmacokinetic properties of buprenorphine and naloxone in the Chinese population
A single-dose phase I study in healthy Chinese subjects and a multi-dose study in Chinese subjects treated for opioid dependence withdrawal described the pharmacokinetic profile of buprenorphine, norbuprenorphine, and naloxone following buprenorphine/naloxone sublingual tablet administration. The buprenorphine/naloxone sublingual tablet doses evaluated in the single-dose study were 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, 12 mg/3 mg, 16 mg/4 mg, and 24 mg/6 mg. The buprenorphine/naloxone sublingual tablet dose levels examined in the multiple-dose study were 16 mg/4 mg and 24 mg/6 mg. The buprenorphine, norbuprenorphine, and naloxone doses in the multiple-dose study were The steady-state pharmacokinetic parameters of buprenorphine, norbuprenorphine and naloxone in the multi-dose study were generally consistent with those reported in the single-dose study in Chinese subjects. The Cmax of buprenorphine and naloxone was slightly higher (up to two times higher) in Chinese subjects than in Western subjects. The higher Cmax values in Chinese subjects may reflect variability across subjects and across studies. In Chinese and Western subjects, other pharmacokinetic parameters (AUC, Tmax, half-life, etc.) were consistent for all three substances to be tested.
) were consistent.
Storage】Sealed at no more than 25℃, with brief exposure to 30℃ in transit allowed.
Packaging
Paper/Aluminium – PVC/Aluminium/nylon blister pack.
7 tablets per plate, 1 plate per box; 7 tablets per plate, 4 plates per box.
[Expiration date].
36 months
【Execution standard
Imported drug registration standard: JM20180003
【Imported drug registration certificate number
1) 2mg/0.5mg: XXXXXXXXXXXXXX
2) 8mg/2mg: XXXXXXXXXXXXXX
Psychotropic substance import permit number]
1) 2mg/0.5mg: XXXXXXXXXXX
2) 8mg/2mg: XXXXXXXXXXXXX
Manufacturer
Licensee’s name: Indivior UK Limited
Licensee’s address: 103 – 105 Bath Road, Slough, Berkshire, SL1 3UH, United Kingdom
Manufacturer’s name: Reckitt Benckiser Healthcare (UK) Ltd
Manufacturer’s address: Dansom Lane, Hull, East Yorkshire, HU8 7DS, United Kingdom
Telephone number: +86 10800 4100 020, +86 10800 7410 023
Fax number: +65 6722 5011
Website: http://www.indivior.com
[email protected]