Mylan-Buprenorphine/Naloxone Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults

Mylan-Buprenorphine/Naloxone (buprenorphine and naloxone) is indicated for substitution treatment in adults with problematic opioid drug dependence.

Geriatrics (>65 years of age)

The safety and efficacy of buprenorphine and naloxone sublingual tablets have not been established in adults over 65 years of age. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, respiratory or cardiac function, concomitant disease or other drug therapy (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

Pediatrics (<18 years of age)

The safety and efficacy of buprenorphine and naloxone in patients below the age of 18 years have not been established, therefore Mylan-Buprenorphine/Naloxone is not recommended in this patient population.

Physician Prescribing Information

Patients prescribed Mylan-Buprenorphine/Naloxone should be carefully monitored within a framework of medical, social, and psychological support as part of a comprehensive opioid dependence treatment program.

Mylan-Buprenorphine/Naloxone sublingual tablets should only be prescribed by physicians who meet the following requirements:

1. i) Experience in substitution treatment in opioid drug dependence, and
2. ii) Completion of a recognized Buprenorphine and Naloxone Education Program.

The Buprenorphine and Naloxone Education Program is a risk management program that is founded on the following four core components that provide for the safe and effective use of the drug within a framework of medical, social and psychological support:

• training of the prescribing physicians in the use of Mylan-Buprenorphine/Naloxone sublingual tablets;
• maintenance of a list of Buprenorphine and Naloxone Education Program trained physicians;
• daily dosing supervised by a healthcare professional, progressing to unsupervised administration as the patient’s clinical stability permits;
• take-home doses once the patient has sufficient clinical stability and is able to safely store Mylan-Buprenorphine/Naloxone. Take-home doses should be assessed and reviewed on a regular basis.

Physicians may obtain more information about the Buprenorphine and Naloxone Education Program by calling the following toll-free phone number: 1-844-596-9526.

CONTRAINDICATIONS

Mylan-Buprenorphine/Naloxone sublingual tablet is contraindicated in:

• Patients who are hypersensitive to buprenorphine, naloxone, or to any ingredient in the formulation. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
• Opioid naïve patients.
• Patients with severe respiratory insufficiency: e.g., acute or severe bronchial asthma, chronic obstructive airway, status asthmaticus, acute respiratory depression, and/or cor pulmonale.
• Patients with severe hepatic impairment.
• Patients with acute alcoholism or delirium tremens.
• Patients with known or suspected mechanical gastrointestinal obstruction (e.g., bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any type).
• Patients with suspected surgical abdomen (e.g., acute appendicitis or pancreatitis).
• Patients with severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury.
• Patients taking monoamine oxidase (MAO) inhibitors (or within 14 days of such therapy).
• Patients with convulsive or seizure disorders.

WARNINGS AND PRECAUTIONS

General

Mylan-Buprenorphine/Naloxone sublingual tablets are indicated for substitution treatment in adults with problematic opioid drug dependence, and, as with other opioid substitution medications, should be used within the framework of medical, social and psychological support as part of a comprehensive opioid dependence treatment program.

Abuse and Misuse Potential

Mylan-Buprenorphine/Naloxone contains buprenorphine, a substance that can be misused or abused in a manner similar to other opioids, legal or illicit, which can lead to overdose and death. This risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines. Consider these risks and the patient’s stability in treatment for opioid use disorder when determining whether Mylan-Buprenorphine/Naloxone is appropriate for the patient. Buprenorphine is sought by people with opioid use disorders and is subject to criminal diversion. This should be considered when prescribing Mylan-Buprenorphine/Naloxone in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.

Prescribe and dispense Mylan-Buprenorphine/Naloxone with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the patient’s home. Clinical monitoring appropriate to the patient’s level of stability and periodic re-evaluation of therapy is essential. Multiple refills should not be prescribed early in treatment and should be given only with appropriate patient follow-up visits.

Monitor all patients receiving Mylan-Buprenorphine/Naloxone and refer patients who have conditions indicative of diversion or progression of opioid dependence and addictive behaviours to more intensive and structured treatments for substance use.

Sub-optimal treatment with Mylan-Buprenorphine/Naloxone may prompt medication misuse by the patient, leading to overdose or treatment dropout. A patient who is under-dosed with Mylan-Buprenorphine/Naloxone may continue responding to uncontrolled withdrawal symptoms by self-medicating with opioids, alcohol or sedative-hypnotics such as benzodiazepines.

The combining of buprenorphine with naloxone in Mylan-Buprenorphine/Naloxone is intended to deter misuse and abuse of the buprenorphine. Intravenous or intranasal misuse of Mylan-Buprenorphine/Naloxone is expected to be less likely than with buprenorphine alone since the naloxone in Mylan-Buprenorphine/Naloxone can precipitate withdrawal in individuals dependent on heroin, methadone, or other opioid agonists.

Some risks of misuse and abuse include overdose, respiratory depression and hepatic injury, and spread of blood borne viral infections.

Extra precautions are required in patients dependent upon concomitant CNS-active substances, including alcohol, and patients with sporadic use of concomitant non-opioid medications (see DOSAGE AND ADMINISTRATION).

Carcinogenesis and Mutagenesis

See TOXICOLOGY section.

Sexual Function/Reproduction

Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility (see ADVERSE REACTIONS, Post-Marketing Experience).

Cardiovascular

Hypotension

Mylan-Buprenorphine/Naloxone may cause orthostatic hypotension in ambulatory patients.

Mylan-Buprenorphine/Naloxone administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines, and other tranquilizers, sedatives/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of Mylan-Buprenorphine/Naloxone.

QTc prolongation

Products containing buprenorphine have been shown to be associated with QTc prolongation (see ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology).

Mylan-Buprenorphine/Naloxone should not be used in patients with a history of Long QT Syndrome or an immediate family member with this condition, or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide), Class IC antiarrhythmic medications (e.g., flecainide, propafenone) or Class III antiarrhythmic medications (e.g. amiodarone).

QTc prolongation may lead to an increased risk of ventricular arrhythmias including torsade de pointes. Torsade de pointes is a polymorphic ventricular tachyarrhythmia. Generally, the risk of torsade de pointes increases with the magnitude of QTc prolongation produced by the drug. Torsade de pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death. Particular care should be exercised when prescribing Mylan-Buprenorphine/Naloxone to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug (see DRUG INTERACTIONS).

Risk factors for torsade de pointes in the general population include, but are not limited to, the following: female gender; age ≥65 years; baseline prolongation of the QTc interval; presence of pathological genetic variants affecting cardiac ion channels or regulatory proteins, especially congenital long QT syndromes; family history of sudden cardiac death at <50 years of age; cardiac disease (e.g., myocardial ischemia or infarction, congestive heart failure, cardiomyopathy, conduction system disease); history of arrhythmias; electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia) or conditions leading to electrolyte disturbances (e.g., persistent vomiting, eating disorders); bradycardia; acute neurological events (e.g., intracranial or subarachnoid haemorrhage, stroke, intracranial trauma); diabetes mellitus; and autonomic neuropathy.

When drugs that prolong the QTc interval are prescribed, healthcare professionals should counsel their patients concerning the nature and implications of the ECG changes, underlying diseases and disorders that are considered to represent risk factors, demonstrated and predicted drug-drug interactions, symptoms suggestive of arrhythmia, risk management strategies, and other information relevant to the use of the drug. Patients should be advised to contact their healthcare provider immediately to report any new chest pain or discomfort, changes in heartbeat, palpitations, dizziness, lightheadedness, fainting, or changes in or new use of other medications.

The use of Mylan-Buprenorphine/Naloxone in patients with circulatory shock should be avoided as it may cause vasodilation that can further reduce cardiac output and blood pressure.

Dependence

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset.

Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.

Abrupt discontinuation of treatment is not recommended as it may result in an opioid withdrawal syndrome that may be delayed in onset. Signs and symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning (see ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, Adjustment or Reduction of Dosage).

Patients who elect to discontinue treatment with Mylan-Buprenorphine/Naloxone should be monitored for withdrawal signs and symptoms.

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy (see WARNINGS AND PRECAUTIONS).

Gastrointestinal Effects

Buprenorphine, a component of Mylan-Buprenorphine/Naloxone, and other morphine-like opioids have been shown to decrease bowel motility and increase intracholedochal pressure. Mylan-Buprenorphine/Naloxone may obscure the diagnosis or clinical course of patients with acute abdominal conditions and should be administered with caution to patients with dysfunction of the biliary tract.

Neonatal Opioid Withdrawal Syndrome (NOWS)

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike the opioid withdrawal syndrome in adults, the NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly.

NOWS may present as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of NOWS may vary. Due to the long half-life of buprenorphine, neonatal monitoring for several days should be considered at the end of pregnancy to minimize the risk of respiratory depression or withdrawal syndrome in neonates. Based on the currently available data, the incidence of NOWS is not clear and there does not appear to be a dose-response relationship.

Advise pregnant women receiving opioid addiction treatment with Mylan-Buprenorphine/Naloxone of the risk of NOWS and ensure that appropriate treatment for the newborn will be available.

This risk of NOWS and the risk of exposure to Mylan-Buprenorphine/Naloxone during pregnancy must be balanced against the risk of untreated opioid addiction. The decision to discontinue Mylan-Buprenorphine/Naloxone therapy during pregnancy should be made as part of a comprehensive treatment plan (see Special Populations, Pregnant Women).

Neurologic Effects

Interactions with Central Nervous System Depressants (including benzodiazepines and alcohol): Buprenorphine should be used with caution during concomitant administration of other opioids, general anesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, benzodiazepines, centrally-active anti-emetics and other CNS depressants. Respiratory depression, hypotension and profound sedation, coma or death may result (see SERIOUS WARNINGS AND PRECAUTIONS, Interaction with Alcohol and Interaction with other Central Nervous System Depressants).

Observational studies have demonstrated that concomitant use of opioids and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioids (see DRUG INTERACTIONS). If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Mylan-Buprenorphine/Naloxone is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see DRUG INTERACTIONS).

Mylan-Buprenorphine/Naloxone should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects, including death (see CONTRAINDICATIONS and ADVERSE REACTIONS, Sedation, and DRUG INTERACTIONS).

Serotonin Syndrome:

Mylan-Buprenorphine/Naloxone could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g. anti-depressants, migraine medications). Treatment with the serotoninergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Mylan-Buprenorphine/Naloxone should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John’s Wort) due to the risk of serotonergic syndrome (see DRUG INTERACTIONS).

Impairment of Ability to Drive or Operate Machinery

Mylan-Buprenorphine/Naloxone may impair the mental and/or physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery.

Patients should be cautioned about operating hazardous machinery and automobiles, until they are reasonably certain that Mylan-Buprenorphine/Naloxone therapy does not adversely affect their ability to engage in such activities.

Mylan-Buprenorphine/Naloxone may cause orthostatic hypotension, drowsiness, dizziness, or impaired thinking, especially during treatment induction and dose adjustment. If used together with alcohol or central nervous system depressants (such as benzodiazepines, tranquilizers, sedatives or hypnotics), the effect is likely to be more pronounced.

Elevation of Cerebrospinal Fluid Pressure

Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with a history of seizure, head injury, intracranial lesions, and other circumstances when cerebrospinal fluid pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness, or changes in the perception of pain as a symptom of disease and may interfere with patient evaluation or obscure the diagnosis or clinical course of concomitant disease. As buprenorphine is an opioid, pain as a symptom of disease may be attenuated.

Peri-Operative Considerations

Mylan-Buprenorphine/Naloxone is not indicated for the treatment of pain. For patients that may require pain management in the post-operative period, please see DRUG INTERACTIONS, opioid analgesic.)

Life-Threatening Respiratory Depression: OVERDOSE

Clinically significant respiratory depression and death may occur in patients receiving Mylan-Buprenorphine/Naloxone. A number of cases of death due to respiratory depression have been reported, particularly when buprenorphine was used by IV route and in combination with benzodiazepines, when high dose buprenorphine was administered to individuals not physically dependent on opioids, or with concomitant administration of buprenorphine with other depressants such as alcohol or other opioids. Deaths have also been reported in association with concomitant administration of buprenorphine and other CNS depressants. Patients should be warned of the potential danger of the self-administration of benzodiazepines or other depressants while under treatment with Mylan-Buprenorphine/Naloxone, particularly when Mylan-Buprenorphine/Naloxone is misused or abused.

Infants exposed in-utero or through breast milk are at risk of life-threatening respiratory depression upon delivery or when nursed (see Special Populations).

Mylan-Buprenorphine/Naloxone may cause severe, possibly fatal, respiratory depression in children who accidentally ingest it. Protect children against exposure and access (see SPECIAL HANDLING INSTRUCTIONS).

Mylan-Buprenorphine/Naloxone should be used with caution in patients with compromised respiratory function (e.g., decreased respiratory reserve, hypoxia, hypercapnia, or kyphoscoliosis), in the elderly and in debilitated patients. Patients with the physical and/or pharmacological risk factors above should be monitored, and dose reduction may be considered.

In the case of overdose, primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, as required. In patients with respiratory depression, symptomatic treatment following standard intensive care measures should be instituted (see OVERDOSAGE).

Hepatic Effects

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through 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, hepatic encephalopathy and death. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment are recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, Mylan-Buprenorphine/Naloxone may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated.

Immune

Allergic Reactions

Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience. The most common signs and symptoms include rashes, urticaria, and pruritus. Cases of bronchospasm, angioedema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine or naloxone or any component of the formulation is a contraindication to Mylan-Buprenorphine/Naloxone use.

Precipitation of opioid withdrawal syndrome

Because of the partial agonist properties of buprenorphine, Mylan-Buprenorphine/Naloxone can precipitate withdrawal symptoms in opioid-dependent patients if administered before the agonist effects resulting from recent opioid use or misuse have subsided. Because it contains naloxone, Mylan-Buprenorphine/Naloxone may produce marked and intense withdrawal signs and symptoms if misused or abused intranasally or by injection by individuals dependent on full opioid agonists such as heroin, morphine or methadone.

To avoid precipitating an opioid withdrawal syndrome during induction onto Mylan-Buprenorphine/Naloxone from short-acting or long-acting opioids, the patient should show objective signs and symptoms of at least moderate withdrawal prior to induction dosing. For example, a moderate score of withdrawal, equal or greater than 13 on the Clinical Opiate Withdrawal Scale (COWS) may be a useful reference assessment.

Withdrawal symptoms may also be associated with sub-optimal dosing.

General Precautions

As with other opioids, Mylan-Buprenorphine/Naloxone should be used with caution in patients with the following conditions:

• myxedema, hypothyroidism, or adrenal cortical insufficiency (e.g. Addison's disease);
• toxic psychoses;
• hypotension, prostatic hypertrophy or urethral stricture.

Opioid-induced miosis, changes in the level of consciousness, or changes in the perception of pain as a symptom of disease, may interfere with patient evaluation or obscure the diagnosis or clinical course of concomitant disease. Opioids should be administered with caution to elderly or debilitated patients (see Special Populations and Conditions).

Special Populations

Pregnant Women

Limited published data from clinical trials, observational studies, and case reports on the use of buprenorphine in pregnancy do not indicate an increased risk of major malformations. Buprenorphine can cross the placental barrier and can be life-threatening to the fetus. There are no adequate and well-controlled studies of Buprenorphine and Naloxone Sublingual Tablets use in pregnant women; therefore, it should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal Opioid Withdrawal Syndrome (NOWS), unlike opioid withdrawal syndrome in adults, may be life-threatening (see WARNINGS AND PRECAUTIONS, Neonatal Opioid Withdrawal Syndrome (NOWS)).

Pregnant women using Mylan-Buprenorphine/Naloxone should not discontinue their medication abruptly as this can cause pregnancy complication such as miscarriage or still-birth. If Mylan-Buprenorphine/Naloxone is discontinued, tapering should be slow and under medical supervision to avoid serious adverse events to the fetus, withdrawal symptoms in the pregnant woman and potential relapse to illicit drug use. The decision to discontinue Mylan-Buprenorphine/Naloxone therapy during pregnancy should be made by the prescriber, patient, and counsellor/support staff as part of a comprehensive treatment plan. The risk of relapse following withdrawal of treatment should be considered (see WARNINGS AND PRECAUTIONS). Healthcare professionals should continue to meet with patients throughout their pregnancy to monitor the management of the opioid addiction, to minimize the risk of reintroducing opioids and to reinstate Mylan-Buprenorphine/Naloxone at the appropriate dose if required (see DOSAGE AND ADMINISTRATION).

Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant doses. Pre-and postnatal development studies in rats demonstrated dystocia, increased neonatal deaths, and developmental delays. No clear teratogenic effects were seen with a range of doses equivalent to or greater than the human dose. However, in a few studies, some events such as acephalus, omphalocele, and skeletal abnormalities were observed but these findings were not clearly treatment-related. Embryo-fetal death was also observed in both rats and rabbits.

Labor and Delivery

Since opioids can cross the placental barrier and are excreted in breast milk, Mylan-Buprenorphine/Naloxone is not recommended to be used in nursing women and during labour and delivery unless, in the judgement of the physician, the potential benefits outweigh the risks. Life-threatening respiratory depression may occur in the newborn if any opioid is administered to the mother during pregnancy. This risk is further increased if another opioid is administered during labour and delivery. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate. Naloxone dosing in neonates should be conducted with caution to avoid triggering an iatrogenic acute NOWS (see WARNINGS AND PRECAUTIONS, Neonatal Opioid Withdrawal Syndrome (NOWS)).

Nursing Women

There are no data on the combination product buprenorphine/naloxone in breastfeeding, however oral absorption of naloxone is limited. Buprenorphine and its metabolite norbuprenorphine are excreted in human milk and infant urine. Limited data from two published studies that included 13 lactating women in total, who were maintained on a sublingual dose of 2.4 to 24 mg/day, did not report adverse reactions in infants exposed to buprenorphine through breast milk and suggest that infant buprenorphine exposure through breast milk is less than 1% of the maternal daily dose.

Caution should be exercised when Mylan-Buprenorphine/Naloxone is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Mylan-Buprenorphine/Naloxone and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. Nursing mothers taking Mylan-Buprenorphine/Naloxone should be advised to monitor the infant for increased drowsiness and breathing difficulties and infants should be regularly monitored by a health care professional.

Life-threatening respiratory depression may occur in the neonate if opioids are administered to a nursing mother.

Pediatrics (< 18 years of age)

Mylan-Buprenorphine/Naloxone is not recommended for use in patients below the age of 18 years. The safety and efficacy of Mylan-Buprenorphine/Naloxone in children have not been established.

Geriatrics (> 65 years)

The safety and efficacy of Mylan-Buprenorphine/Naloxone in elderly patients over 65 years of age have not been established.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and titrating upwards slowly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

Patients with Hepatic Impairment:

Mylan-Buprenorphine/Naloxone is contraindicated in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. If Mylan-Buprenorphine/Naloxone is used in this patient population, caution is advised (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Both buprenorphine and naloxone are extensively metabolized by the liver. In patients with moderate and severe hepatic impairment, plasma levels and half-life values of both buprenorphine and naloxone were found to be markedly increased compared to healthy subjects. This effect was more pronounced in patients with severe hepatic impairment.

Hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, and the doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. Dose adjustments may be considered in cases of mild to moderate hepatic impairment, and patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of naloxone and / or buprenorphine.

As with other opioids, buprenorphine has been shown to increase intracholedochal pressure and should therefore be administered with caution to patients with dysfunction of the biliary tract.

Patients with Renal Impairment:

Renal elimination plays a relatively minor role (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency) in the overall clearance of buprenorphine; therefore, dose modification based on renal function is generally not required. However, metabolites of buprenorphine accumulate in patients with advanced renal failure. Caution is recommended when dosing patients with severe renal impairment (CLcr <30 ml/min) which may require dose adjustment.

The effects of renal failure on naloxone pharmacokinetics are unknown.

Endocrine

Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following long term use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.

Monitoring and Laboratory Tests

Baseline liver function tests and documentation of viral hepatitis status are recommended prior to commencing therapy. Regular monitoring of liver function is recommended. Patients who are positive for viral hepatitis, on concomitant medicinal products and/or have existing liver dysfunction are at greater risk of liver injury.

Information for Patients

• Patients should be advised to keep Mylan-Buprenorphine/Naloxone out of reach and sight of children to prevent accidental ingestion that can result in death. Patients should be advised not to take this medicine in front of children. Patients should be advised that if a child is exposed to Mylan-Buprenorphine/Naloxone sublingual tablets, medical attention should be sought immediately.
• Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines, sedatives, tranquilizers, antidepressants or alcohol while taking Mylan-Buprenorphine/Naloxone, which may result in serious harm or death. Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use them only as directed by their physician.
• Patients should inform their physician if other prescription medications are currently being used or are prescribed for future use.

• Patients should be cautioned to keep their tablets in a safe place, and to protect them from theft. Patients should be advised never to give Mylan-Buprenorphine/Naloxone sublingual tablets to anyone else, as it may cause harm or death. Selling or giving away this medicine is

  • against the law.
• Patients should inform their family members that, in the event of overdose, the treating physician or emergency staff should be informed that the patient is physically dependent on narcotics and is being treated with Mylan-Buprenorphine/Naloxone.
• Patients should be cautioned about driving a car or operating hazardous machinery, including automobiles, until they are reasonably certain that Mylan-Buprenorphine/Naloxone therapy does not adversely affect their ability to engage in such activities. Mylan-Buprenorphine/Naloxone may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating machinery, especially during drug induction and dose adjustment.
• Patients should be cautioned that, like other opioids, Mylan-Buprenorphine/Naloxone may cause orthostatic hypotension in ambulatory individuals.
• Patients should be advised to take Mylan-Buprenorphine/Naloxone sublingual tablets once a day. Patients should be advised not to change the dosage of Mylan-Buprenorphine/Naloxone sublingual tablets without consulting their physician.
• Patients should be informed that Mylan-Buprenorphine/Naloxone sublingual tablets can cause opioid drug dependence and that opioid withdrawal signs and symptoms may occur when the medication is discontinued. Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be advised to work closely with their physician on a tapering schedule and should be apprised of the potential to relapse.
• Women of childbearing potential, who become pregnant or are planning to become pregnant, should be advised to consult their physician regarding the possible risks to their baby if they are exposed to Mylan-Buprenorphine/Naloxone sublingual tablets during pregnancy. Patients who are breastfeeding should be warned to monitor the infant for drowsiness and difficulty breathing.
• Athletes should be aware that this medicine may cause a positive reaction to "anti-doping tests" and should inform the authorities that they are being treated with Mylan-Buprenorphine/Naloxone.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Clinically significant respiratory depression and death may occur in patients receiving Mylan-Buprenorphine/Naloxone, particularly when used in combination with benzodiazepines and other CNS depressants such as other opioids or alcohol (see WARNINGS AND PRECAUTIONS).

The most commonly reported treatment related adverse reactions reported during the pivotal clinical studies were headache and signs and symptoms commonly associated with drug withdrawal (i.e. abdominal pain, anxiety, diarrhoea, muscle aches, insomnia, headache, constipation, nausea and hyperhidrosis). Some reports of seizure, vomiting, diarrhoea, and elevated liver function tests were considered serious.

In patients with marked opioid dependence, initial administration of Mylan-Buprenorphine/Naloxone can produce a withdrawal effect similar to that associated with naloxone.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In the pivotal clinical study (CR96/013 [double-blind] + CR96/014 [open label extension]), of 472 patients treated with sublingual tablets containing buprenorphine in combination with naloxone, 334 patients were treated for 3 months, 261 patients were treated for greater than 6 months and 100 patients were treated up to one year. The most used dose was 16 mg/day. Treatment-emergent adverse events reported in the pivotal clinical study of buprenorphine and naloxone (≥1.0 % of buprenorphine and naloxone-treated patients) are listed in Table 1.

Table 1 - Treatment-emergent adverse events reported in the pivotal clinical study of Buprenorphine and Naloxone (≥1.0 % of Buprenorphine and Naloxone-treated patients)

The most commonly observed adverse reactions in this study are consistent with opioid withdrawal or agonist effects. Although it is not possible to compare adverse effects across trials because of differences in methodology and patient populations, the undesirable effects observed in other studies are qualitatively similar.

Nausea: Nausea is a common side effect with opioids and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment.

Constipation: Practically all patients become constipated while taking opioids on a persistent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. Stimulant laxatives, stool softeners, and other appropriate measures should be used as required. As fecal impaction may present as overflow diarrhea, the presence of constipation should be excluded in patients on opioid therapy prior to initiating treatment for diarrhea.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Treatment-emergent adverse reactions reported as less common (<1%) in the pivotal buprenorphine and naloxone clinical studies included:

Body as a Whole: carcinoma, cellulitis, chills/fever, hangover, heat stroke, hernia, human immunodeficiency virus (HIV) test positive, hostility, hypothermia, infection fungal, infection parasitic, neoplasia, overdose, pain chest (substernal), pain flank, pain pelvic, photosensitivity, pain rib and suicide attempt.

Cardiovascular System: angina pectoris, bradycardia, electrocardiogram abnormal, hypotension, myocardial infarction, palpitation, phlebitis, tachycardia, thrombosis, thrombophlebitis (deep), vascular disorder and varicose vein.

Digestive System: appetite increased, colitis, dry mouth, dysphagia, eructation, gastritis, gamma glutamyl transpeptidase increased, gingivitis, glossitis, gum hemorrhage, rectal hemorrhage, hematemesis, hepatitis C, rectal disorder, saliva increased, stomatitis/ulcer, tenesmus, tooth caries, ulcer peptic, stomach ulcer hemorrhage and tongue discolouration.

Endocrine System: sexual function abnormal.

Hemic and Lymphatic System: leucocytosis, leucopenia, methemoglobin, thrombocythemia, thrombocytopenia and white blood cells abnormal.

Metabolism and Nutritional Disorders: alanine aminotransferase increased, albuminuria, alkaline phosphatase increased, aspartate aminotransferase increased, blood urea nitrogen increased, creatinine increased, edema, electrolytes abnormal, hypercholesterolemia, hyperlipidemia, hypoglycemia, hypokalemia, lactate dehydrogenase increased, weight increased.

Musculoskeletal System: bursitis, myasthenia, pain bone, spasm general, tendon disorder and tenosynovitis.

Nervous System: amnesia, apathy, convulsion, depersonalization, emotional lability, euphoric mood, hallucination, hyperkinesia, miosis, neuralgia, neuropathy, paralysis facial, speech disorder, stupor, twitch, urinary retention and vertigo.

Respiratory System: emphysema, epistaxis, hemoptysis, hiccup, laryngitis, pleural disorder and voice alteration.

Skin and Appendages: alopecia, exfoliative dermatitis, fungus dermatitis, hair disorder, lichen dermatitis, melanoma skin, neoplasia skin, psoriasis, rash maculopapular, rash vesiculobullous, skin disorder and ulcer skin.

Special Senses: corneal lesion, deafness, ear disorder, otitis media, pain eye, tinnitus.

Urogenital System: amenorrhea, ejaculation abnormal, fibrocystic breast, leukorrhea, mastitis, menorrhagia, menstrual disorder, metrorrhagia, neoplasia breast, nephrolithiasis, orchitis, pain breast, pain kidney, papanikolaou smear suspicious, unintended pregnancy, prostate disorder, salpingitis, testis disorder, urethritis, urination impaired, urinary frequency, and urinary urgency.

Buprenorphine used alone

Buprenorphine used alone for treatment of opioid dependency has been associated with the following signs and symptoms (> 1 %): constipation, headache, insomnia, asthenia, drowsiness, nausea and vomiting, fainting and dizziness, orthostatic hypotension, and sweating. Other adverse events (< 0.1 %) have been reported in association with buprenorphine alone. These are:

• respiratory depression (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS);
• hepatic necrosis and hepatitis (see WARNINGS AND PRECAUTIONS); and
• hallucinations.

Cases of bronchospasm, angioneurotic edema and anaphylactic shock have also been reported.

In cases of drug abuse or intentional drug misuse, some adverse experiences attributed to the act of misuse rather than the medicinal product have included: local reactions, such as cellulitis or abscess that are sometimes septic, potentially serious acute hepatitis, pneumonia, endocarditis, and other serious infections (see WARNINGS AND PRECAUTIONS).

In patients presenting with marked drug dependence, initial administration of buprenorphine can produce a withdrawal effect similar to that associated with naloxone.

NOWS has been reported among newborns of women who have received buprenorphine products during pregnancy. The syndrome may be milder and more protracted than that from short acting full mu-opioid agonists. The nature of the syndrome may vary depending upon the mother’s drug use history (see WARNINGS AND PRECAUTIONS).

Post-marketing Experience

Table 2 lists adverse drug reactions reported during post-marketing surveillance, not reported elsewhere in the label, some of which may have only been observed with buprenorphine alone in the treatment of opioid dependence. Adverse drug reactions are presented by MedDRA System Organ Class in order by preferred term.

Table 2 - Adverse Drug Reactions Collected Through Post-marketing Surveillance

Androgen deficiency: Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

DRUG INTERACTIONS

Overview

Interaction with Benzodiazepines and Other Central Nervous System (CNS) Depressants:

Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants (e.g. other opioids, sedatives/hypnotics, antidepressants, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, phenothiazines, neuroleptics, antihistamines, antiemetics, and alcohol) and beta-blockers, increases the risk of respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation (see WARNINGS AND PRECAUTIONS, Neurologic Effects, Interactions with Central Nervous System Depressants (including benzodiazepines and alcohol) and Impairment of Ability to Drive or Operate Machinery). Mylan-Buprenorphine/Naloxone should not be consumed with alcohol as it may increase the chance of experiencing dangerous side effects.

Drug-Drug Interactions

The use of alcohol while taking Mylan-Buprenorphine/Naloxone should be avoided.

Alcohol

Alcohol increases the sedative effect of opioids. Alcoholic beverages should be avoided while taking Mylan-Buprenorphine/Naloxone. Medication containing alcohol should be co-administered with caution (see WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions Box).

Mylan-Buprenorphine/Naloxone should be used cautiously when co-administered with:

Benzodiazepines

This combination may result in death due to respiratory depression of central origin, therefore patients should be closely monitored when prescribed this combination. This combination must be avoided where there is risk of misuse or abuse. Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking Mylan-Buprenorphine/Naloxone, and should also be cautioned to use benzodiazepines concurrently with this product only as prescribed (see WARNINGS AND PRECAUTIONS).

Other central nervous system depressants

Combining central nervous system depressants with buprenorphine increases central nervous system depressant effects. The reduced level of alertness can make driving and using machines hazardous. Example central nervous system depressants are: other opioids (e.g. methadone, analgesics, antitussives), certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics, neuroleptics, clonidine and related substances.

Opioid analgesics

The analgesic properties of other opioids may be reduced in patients receiving treatment with buprenorphine/naloxone for opioid dependence. Adequate analgesia may be difficult to achieve when administering a full opioid agonist in patients receiving Mylan-Buprenorphine/Naloxone. Conversely, the potential for overdose should be considered with higher than usual doses of full agonist opioids, such as methadone or analgesics, especially when attempting to overcome buprenorphine partial agonist effects, or when buprenorphine plasma levels are declining. Patients with a need for analgesia and opioid dependence treatment may be best managed by multidisciplinary teams that include both pain and opioid dependence treatment specialists (see Precipitation of opioid withdrawal syndrome).

Naltrexone and other opioid antagonists

Patients maintained on Mylan-Buprenorphine/Naloxone may experience a sudden onset of prolonged and intense opioid withdrawal symptoms if dosed with opioid antagonists that achieve pharmacologically relevant systemic concentrations.

Since buprenorphine is a partial mu-opioid agonist, concomitantly administered opioid antagonists such as naltrexone can reduce or completely block the effects of buprenorphine/naloxone.

CYP3A4 inhibitors

Patients receiving buprenorphine should be closely monitored, and may require dose reduction if combined with potent 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 (50% and 70% respectively) and, to a lesser extent, of norbuprenorphine. Example CYP3A4 inhibitors include protease inhibitors, macrolide antibiotics, and azole antifungals.

CYP3A4 inducers

Concomitant use of CYP3A4 inducers with buprenorphine may decrease buprenorphine plasma concentrations, potentially resulting in under-treatment of opioid dependence with buprenorphine. It is recommended that patients receiving Mylan-Buprenorphine/Naloxone should be closely monitored if inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered, and the dose of buprenorphine or CYP3A4 inducer may need to be adjusted accordingly.

Monoamine oxidase inhibitors (MAOI)

The concomitant use of MAOIs may produce exaggeration of the effects of opioids.

Serotonin Syndrome

Coadministration of buprenorphine/naloxone with a serotonergic agent, such as a Selective Serotonin Re-uptake Inhibitor or a Serotonin Norepinephrine Re-uptake Inhibitor, may increase the risk of serotonin syndrome, a potentially life-threatening condition (see WARNINGS AND PRECAUTIONS).

QTc Interval-Prolonging Drugs

The concomitant use of Mylan-Buprenorphine/Naloxone with other QTc interval-prolonging drugs should be avoided (see WARNINGS AND PRECAUTIONS, Cardiovascular; ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology). Drugs that have been associated with QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QTc interval prolongation and/or torsade de pointes: Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide), Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide, dronedarone), Class 1C antiarrhythmics (e.g., flecainide, propafenone), antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone, risperidone), antidepressants (e.g., fluoxetine, citalopram, tricyclic/tetracyclic antidepressants [e.g., amitriptyline, imipramine, maprotiline]), opioids (e.g., methadone), macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, azithromycin, tacrolimus), quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin), pentamidine, antimalarials (e.g., quinine, chloroquine), azole antifungals (e.g., ketoconazole, fluconazole, voriconazole), domperidone, angrelide, ivabradine, 5-hydroxytryptamine (5-HT)3 receptor antagonists (e.g., ondansetron), tyrosine kinase inhibitors (e.g., sunitinib, nilotinib, ceritinib, vandetanib), arsenic trioxide, histone deacetylase inhibitors (e.g., vorinostat), beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol).

Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuretics and/or effects on blood pressure and increase the dosage of the diuretic, as needed.

Anticholinergics

Concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility.

Antiretrovirals

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A4 inducers, whereas delaviridine is a CYP3A4 inhibitor. Significant pharmacokinetic interactions between NNRTIs and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. Exercise caution when prescribing and therapeutic concentration monitoring is recommended.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

Alcohol

Alcohol can increase the sedative effect of opioids. Alcoholic beverages should be avoided while taking Mylan-Buprenorphine/Naloxone.

DOSAGE AND ADMINISTRATION

Mylan-Buprenorphine/Naloxone sublingual tablets should be placed under the tongue until dissolved. Altering the tablet to take it by routes other than the indicated sublingual route can lead to serious adverse events including death. Do not cut, break, crush or chew Mylan-Buprenorphine/Naloxone (see WARNINGS AND PRECAUTIONS).

Adults:

Mylan-Buprenorphine/Naloxone is indicated for substitution treatment in adults with problematic opioid drug dependence. The intention of the naloxone component is to deter injection and intranasal misuse and abuse.

Opioid drug dependence is a chronic relapsing disease; length of treatment must be tailored for each patient depending on his/her condition.

Patients prescribed Mylan-Buprenorphine/Naloxone should be carefully monitored within a framework of medical, social, and psychological support as part of a comprehensive opioid dependence treatment program.

Mylan-Buprenorphine/Naloxone sublingual tablets should only be prescribed by physicians who meet the following requirements:

1. i) Experience in substitution treatment in opioid drug dependence, and
2. ii) Completion of a recognized Buprenorphine and Naloxone Education Program.

The Buprenorphine and Naloxone Education Program is a risk management program that is founded on the following four core components that provide for the safe and effective use of the drug within a framework of medical, social and psychological support:

• training of the prescribing physicians in the use of Mylan-Buprenorphine/Naloxone sublingual tablets;
• maintenance of a list of Buprenorphine and Naloxone Education Program trained physicians;
• daily dosing supervised by a healthcare professional, progressing to unsupervised administration as the patient’s clinical stability permits;
• take-home doses once the patient has sufficient clinical stability and is able to safely store Mylan-Buprenorphine/Naloxone. Take-home doses should be assessed and reviewed on a regular basis.

Physicians should not prescribe Mylan-Buprenorphine/Naloxone sublingual tablets unless the condition of daily intake supervised by a healthcare professional can be ensured until the patient has sufficient clinical stability and is able to safely store Mylan-Buprenorphine/Naloxone take-home doses (see WARNINGS AND PRECAUTIONS).

Physicians may obtain more information about the Buprenorphine and Naloxone Education Program by calling the following toll-free phone number: 1-844-596-9526.

Dosing Considerations

Method of Administration

Mylan-Buprenorphine/Naloxone sublingual tablets should be placed under the tongue until dissolved. Dissolution usually occurs within 2 to 10 minutes.

When multiple tablets are needed to achieve optimal dosage, a patient may place all tablets sublingually at the same time or in two divided portions, the second portion to be placed sublingually directly after the first portion has dissolved.

Patients should not swallow or consume food or drink until the tablet is completely dissolved.

Precautions to be taken before induction

Prior to induction with Mylan-Buprenorphine/Naloxone, 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 or level of opioid dependence. To avoid precipitating withdrawal, induction with Mylan-Buprenorphine/Naloxone should be undertaken when objective and clear signs of withdrawal are evident.

Patients taking heroin (or other short-acting opiates):

For patients dependent on heroin or short-acting opioids, the first dose of Mylan-Buprenorphine/Naloxone should be started when objective signs of withdrawal appear, but not less than 6 hours after the patient last used opioids. A score equal or greater than 13 on the Clinical Opiate Withdrawal Scale (COWS) may be a useful reference assessment.

Patients on methadone:

For patients receiving methadone, the methadone maintenance dose should be reduced to the minimum methadone daily dose that the patient can tolerate before beginning Mylan-Buprenorphine/Naloxone therapy. The first Mylan-Buprenorphine/Naloxone dose should be started only when objective signs of withdrawal appear (e.g. COWS score equal or greater than 13), and generally not less than 24 hours after the patient last used methadone because of the long half-life of methadone.

Baseline liver function tests and documentation of viral hepatitis status are recommended prior to commencing therapy. Regular monitoring of liver function is recommended.

Patients who have been opioid abstinent and wish to return to treatment should initiate with 2 mg Mylan-Buprenorphine/Naloxone and then titrate per physician’s judgement.

Recommended Dose and Dosage Adjustment

Induction:

The recommended starting dose is 8 mg Mylan-Buprenorphine/Naloxone on Day 1, initiating with 4 mg and then an additional 4 mg dose may be administered depending on the individual patient’s requirement. The suggested total dose target for treatment on Day 1 is within the range of 8 and 12 mg.

During initiation of treatment, closer dosing supervision is recommended to ensure proper sublingual placement of the dose and to observe patient response to treatment as a guide to effective dose titration according to clinical effect.

Patients who have been opioid abstinent and wish to return to treatment should initiate with 2 mg Mylan-Buprenorphine/Naloxone and then titrate per physician’s judgement.

Patients with Hepatic Impairment:

Mylan-Buprenorphine/Naloxone is contraindicated in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. Dose adjustments may be considered in cases of mild to moderate hepatic impairment, and patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of naloxone and / or buprenorphine (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Patients with Renal Impairment:

Caution is recommended when dosing patients with severe renal impairment (CL_cr <30 ml/min) which may require dose adjustment.

Geriatrics (>65 years of age):

Respiratory depression has occurred in the elderly when opioids were co-administered with other agents that can depress respiration. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and titrating upwards slowly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

Patients who are Pregnant and during the Postpartum Period:

Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Withdrawal signs and symptoms should be monitored closely, and the dose adjusted as necessary. If the pregnant woman has chosen to discontinue treatment at any point during her pregnancy or postpartum period (see Reducing dosage and terminating treatment (Medical taper)), and subsequently choses to reinstate; the treatment should be initiated with 2 mg and then titrate per physician’s judgement.

Dose Titration:

Dosage stabilisation and maintenance therapy

Following treatment induction, the patient should be rapidly stabilised on an adequate maintenance dose by titrating to clinical effect. Dose titration in increments or decrements of 2 - 8 mg buprenorphine to a level that holds the patient in treatment and suppresses opioid withdrawal effects is guided by reassessment of the clinical and psychological status of the patient.

Clinical studies have shown that a maintenance dose of 12 mg to 16 mg of Buprenorphine/Naloxone used once daily is clinically effective for most patients. Doses should not exceed a maximum single daily dose of 24 mg.

During maintenance therapy, it may be necessary to periodically re-stabilise the patient to a new maintenance dose in response to changing patient needs.

Less than daily dosing:

Following successful induction and after the patient is receiving a stable dose, the frequency of Mylan-Buprenorphine/Naloxone dosing may be decreased to dosing every other day at twice the individually titrated daily dose. For example, a patient who receives a stable daily dose of 8 mg may be given 16 mg on alternate days, with no medication on the intervening days. However, the dose given on any one day should not exceed 24 mg.

In some patients, following successful induction and after the patient is receiving a stable dose, the frequency of Mylan-Buprenorphine/Naloxone dosing may be decreased to 3 times a week (for example on Monday, Wednesday and Friday). The dose on Monday and Wednesday should be twice the individually titrated daily dose, and the dose on Friday should be three times the individually titrated daily dose, with no medication on the intervening days. However, the dose given on any one day should not exceed 24 mg. Patients requiring a titrated daily dose > 8 mg/day may not find this regimen adequate.

Patients dependent upon concomitant CNS-active substances, including alcohol, should not be treated with the increased doses required by the less-than-daily dosing regimen intended for use in a supervised dose setting. Patients with sporadic use of concomitant non-opioid medications should be monitored closely, and all patients dosed on a less-than-daily basis should be observed for at least 1.5 hours following the first multi-dose administration initiating less-than-daily dosing.

Reducing dosage and terminating treatment (Medical taper):

The decision to discontinue therapy with Mylan-Buprenorphine/Naloxone should be made as part of a comprehensive treatment plan. To avoid withdrawal symptoms and potential relapse to illicit drug use, the Mylan-Buprenorphine/Naloxone dose may be progressively decreased over time in favourable cases until treatment can be discontinued. The decision to taper should be made by the prescriber, patient, and counsellor/support staff. The risk of relapse following withdrawal of treatment should be considered (see WARNINGS AND PRECAUTIONS).

To avoid overdose, patients should be informed that reducing and/or discontinuing any opioids including Mylan-Buprenorphine/Naloxone decreases their tolerance to these drugs. If treatment needs to be re-initiated, the patient must start at the lowest dose and titrate up to avoid overdose.

Clinical Supervision

Treatment should be initiated with supervised administration progressing to unsupervised administration as the patient’s clinical stability permits. During the initiation of treatment, closer supervision of dosing is recommended to ensure proper sublingual placement of the dose and to observe patient response to treatment as a guide to effective dose titration according to clinical effect.

As the patient becomes stabilised in treatment, longer intervals between patient assessments may be appropriate based upon patient compliance with treatment, effectiveness of the treatment plan, and overall patient progress. It is also recommended that the prescription quantity for unsupervised administration be determined with consideration for the frequency of patient visits and the patient’s ability to manage supplies of take-home medication.

DRUG ABUSE AND DEPENDENCE

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence with or without psychological dependence, characterized by withdrawal upon abrupt discontinuation or rapid taper. Withdrawal (abstinence) symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning. The withdrawal syndrome is milder than seen with full agonists and may be delayed (see WARNINGS AND PRECAUTIONS).

Abuse and diversion of buprenorphine by opiate addicts has been reported (see WARNINGS AND PRECAUTIONS).

Disposal

Unused or expired Mylan-Buprenorphine/Naloxone sublingual tablets should be properly disposed of to prevent accidental exposure to others, including children or pets. If temporary storage is required before disposal, a sealed child-proof container, such as a biohazard waste container or a lockable medication box could be obtained from a pharmacy.

Mylan-Buprenorphine/Naloxone should never be disposed of in household trash. Disposal via a pharmacy take-back program is recommended. Consult with a pharmacist and/or consult with www.healthsteward.ca for information on responsible pharmaceutical disposal options.

Missed Dose

Missed doses are notable as they may contribute to a loss of tolerance to buprenorphine. The more doses a patient misses, the greater the loss of tolerance. Patients should be reassessed to ensure they are receiving an appropriate dose on resumption of Mylan-Buprenorphine/Naloxone treatment. The resumption dose may need to be adjusted back to levels used during Mylan-Buprenorphine/Naloxone induction (see Recommended Dose and Dosage Adjustment, Induction).

If the patient has relapsed to full agonist opioids, the patient should be advised to suspend resumption of their Mylan-Buprenorphine/Naloxone until they are in moderate opioid withdrawal due to the risk of precipitated withdrawal.

OVERDOSAGE

Signs and symptoms: Signs and symptoms of acute overdose include miosis, sedation, hypotension, respiratory depression and death. Nausea and vomiting may be observed.

The major symptom requiring intervention is respiratory depression, which could lead to respiratory arrest and death.

Treatment:

In the event of overdose, general supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient. Symptomatic treatment of respiratory depression, following standard intensive care measures, should be performed. A patent airway and assisted or controlled ventilation must be assured. The patient should be transferred to an environment where full resuscitation facilities are available.

If the patient vomits, care must be taken to prevent aspiration of the vomitus.

Due to the extremely slow dissociation of buprenorphine from opioid receptors, naloxone even at high doses of 10-35 mg/70kg may be of limited value in the management of buprenorphine overdose. Use of an opioid antagonist (e.g., naloxone) is nevertheless recommended, despite the modest effect it may have in reversing the respiratory symptoms of buprenorphine compared to its effects on full agonist opioid agents.

If naloxone is used, the long duration of action of buprenorphine should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Naloxone can be cleared more rapidly than buprenorphine, allowing for a return of previously controlled buprenorphine overdose symptoms, so a continuing infusion may be necessary. Ongoing IV infusion rates should be titrated to patient response. If infusion is not possible, repeated dosing with naloxone may be required. Carefully monitor the patient until spontaneous respiration is reliably re-established. Even in the face of improvement, continued medical monitoring is required for at least 24 hours because of the possibility of extended effects of buprenorphine.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Buprenorphine has a high affinity for mu-opioid receptors, therefore reducing the binding ability, and thus the activity, of other opioids on these receptors. Buprenorphine’s activity in opioid maintenance treatment is attributed to its slowly reversible link with the mu-opioid receptors in the brain, which prolongs activity at the receptor, leading to reduced opioid withdrawal symptoms.

Naloxone is an antagonist at mu, delta, and kappa-opioid receptors. Because of its almost complete first pass metabolism and low sublingual bioavailability, naloxone administered orally or sublingually has no detectable pharmacological activity. However, if misused or abused intranasally or by injection by a person dependent upon a full opioid agonist, the presence of naloxone in Mylan-Buprenorphine/Naloxone can produce marked opioid antagonist effects that can prompt the immediate onset of opioid withdrawal symptoms as a deterrent to misuse and abuse.

Pharmacodynamics

Subjective effects

Comparison of buprenorphine with full agonists such as methadone and hydromorphone suggest that sublingual buprenorphine produces typical opiate agonist effects, which are limited by a ceiling effect.

Buprenorphine 16 mg had opioid agonist effects similar to 4 mg intramuscular hydromorphone, and equivalent to about 30 mg intramuscular morphine.

Opioid agonist ceiling effects were also observed in a double-blind parallel group, dose ranging comparison of single doses of 1, 2, 4, 8, 16 or 32 mg buprenorphine sublingual solution (comparable approximately to 1.5 mg, 3 mg, 6 mg, 12 mg, 24 mg and 48 mg, respectively, of the tablet form), oral methadone (15, 30, 45 or 60 mg) and placebo. The treatments were given in ascending dose order at intervals of at least one week to 16 opioid experienced, non-dependent male subjects. Both drugs produced typical opioid agonist effects. For all measures for which drugs produced an effect, buprenorphine produced a dose-related response but, in each case, there was a dose which produced no further effects. In contrast, the highest dose of methadone (60 mg) always produced the greatest effects.

Physiologic effects

Buprenorphine effects were also assessed in opioid-experienced subjects administered 12 mg sublingually or up to 16 mg by IV injection to examine cardiovascular, respiratory and subjective effects at doses comparable to those used for treatment of opioid dependence.

Compared to placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O₂ saturation or skin temperature across time. Systolic blood pressure was higher for the 8 mg buprenorphine IV group than placebo. Minimum and maximum effects were similar across all treatments. Subjects remained responsive to low voice and responded to computer prompts. Some subjects showed irritability, but no other changes were observed.

The respiratory effects of sublingual buprenorphine solution (1, 2, 4, 8, 16 or 32 mg) were compared to those of oral methadone (15, 30, 45 or 60 mg) in non-dependent, opioid experienced healthy male volunteers. In this study, hypoventilation not requiring mechanical intervention was reported more frequently after buprenorphine sublingual solution doses of 4 mg and higher (4 mg solution comparable approximately to a 6 mg tablet dose) than after methadone at these doses tested. Both drugs decreased O2 saturation to the same degree.

Effect of naloxone

Naloxone had no clinically significant effect when administered by the sublingual route; plasma concentrations are low and decline rapidly. Buprenorphine and naloxone, when administered sublingually even to an opioid-dependent population, was recognized as an opioid agonist, whereas when administered intramuscularly, combinations of buprenorphine with naloxone produced opioid antagonist actions similar to naloxone. In methadone-maintained patients and heroin-dependent subjects, IV administration of buprenorphine/naloxone combinations precipitated opioid withdrawal and was perceived as unpleasant and dysphoric. In morphine-stabilized subjects, intravenously administered combinations of buprenorphine with naloxone produced opioid antagonist and withdrawal effects that were ratio-dependent; the most intense withdrawal effects were produced by 2:1 and 4:1 ratio, less intense by an 8:1 ratio. Mylan-Buprenorphine/Naloxone tablets contain buprenorphine with naloxone at a ratio of 4:1.

Central Nervous System:

Opioids produce respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO₂ tension and to electrical stimulation.

Opioids depress the cough reflex by direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.

Opioids cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone overdose.

Gastrointestinal Tract and Other Smooth Muscle:

Opioids cause a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.

Cardiovascular System:

Opioids may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, hyperhidrosis and/or orthostatic hypotension.

Endocrine System:

Opioids may influence the hypothalamic-pituitary-adreno or -gonadal axes. Some changes that can be seen include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes.

Immune System:

In vitro and animal studies indicate that opioids have a variety of effects on immune functions, depending on the context in which they are used. The clinical significance of these findings is unknown.

Pharmacokinetics

Buprenorphine

Absorption: When taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and glucuroconjugation in the small intestine. The use of this medication by the oral route is therefore ineffective.

When taken sublingually, there was a wide inter-patient variability in the absorption of buprenorphine but within subject variability was low. Plasma levels of buprenorphine increased with dose in the range of 2 mg to 16 mg, although the increase was not directly dose proportional. Mean C_max for sublingual tablet doses of 2 mg, 8 mg, 12 mg and 16 mg were, respectively, 0.780, 2.58, 4.60 and 5.51 (ng/mL). Mean AUC_0-inf for sublingual tablet doses of 2 mg, 8 mg, 12 mg and 16 mg were, respectively, 7.651, 25.31, 43.9 and 54.7 (h*ng/mL).

Distribution: Buprenorphine is highly lipophilic, which leads to rapid penetration of the blood-brain barrier. Buprenorphine is approximately 96% protein-bound, primarily to alpha and beta globulin.

Metabolism: Buprenorphine is primarily metabolized through N-dealkylation by liver microsomal CYP3A4. The parent molecule and the primary dealkylated metabolite, norbuprenorphine, undergo subsequent glucuronidation.

Norbuprenorphine binds to opioid receptors in vitro; however, it is not known whether norbuprenorphine contributes to the overall effect of buprenorphine and naloxone.

Excretion: Buprenorphine is eliminated in the feces (~70%) by biliary excretion of the glucuroconjugated metabolites, the rest (~30%) being eliminated in the urine. In feces, almost all of the buprenorphine and norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2% conjugated). In urine, most of buprenorphine and norbuprenorphine were conjugated (buprenorphine, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11% conjugated).

The overall mean elimination half-life of buprenorphine in plasma is ranging from 31 to 42 hours, although the levels are very low 10 hours after dosing (majority of AUC of buprenorphine is captured within 10 hours), indicating that the effective half-life may be shorter.

Naloxone

Absorption: Naloxone mean peak plasma concentrations were achieved at approximately 1 hr post-dose and were measurable up to 8 hours post-dose. Across the doses of 1 mg to 4 mg, a trend towards increasing naloxone plasma exposure with an increase in dose was observed.

Naloxone has not been found to affect the pharmacokinetics of buprenorphine and both buprenorphine alone and buprenorphine/naloxone sublingual tablets deliver similar plasma concentrations of buprenorphine.

Distribution: Following IV administration, naloxone is rapidly distributed (distribution half-life ~ 4 minutes). Following oral administration, naloxone is barely detectable in plasma; following sublingual administration of buprenorphine and naloxone, plasma naloxone concentrations are low and decline rapidly. Naloxone is approximately 32-45% protein bound, primarily to albumin.

Metabolism: The drug is metabolized in the liver, primarily by glucuronide conjugation. Naloxone undergoes direct glucuronidation to naloxone 3-glucuronide, as well as N-dealkylation, and reduction of the 6-oxo group.

Excretion: The drug is excreted in the urine. Naloxone has a mean elimination half-life from plasma ranging from 4 to 8 hours.

Special Populations and Conditions

Pediatrics:

Individuals under 18 years of age should not take Mylan-Buprenorphine/Naloxone tablets.

Geriatrics:

The safety and efficacy of Mylan-Buprenorphine/Naloxone have not been established in adults over 65 years of age.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and titrating upwards slowly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

Mylan-Buprenorphine/Naloxone is contraindicated in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. If Mylan-Buprenorphine/Naloxone is used in this patient population, caution is advised (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Both buprenorphine and naloxone are extensively metabolized by the liver. In patients with moderate and severe hepatic impairment, plasma levels and half-life values of both buprenorphine and naloxone were found to be markedly increased compared to healthy subjects. This effect was more pronounced in patients with severe hepatic impairment.

Hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, and the doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. Dose adjustments may be considered in cases of mild to moderate hepatic impairment, and patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of naloxone and / or buprenorphine.

As with other opioids, buprenorphine has been shown to increase intracholedochal pressure and should therefore be administered with caution to patients with dysfunction of the biliary tract.

Renal Impairment: Renal elimination plays a relatively minor role (~ 30%) in the overall clearance of buprenorphine and naloxone. No dose modification based on renal function is required but caution is recommended when dosing subjects with severe renal impairment.

STORAGE AND STABILITY

Temperature

Store at controlled room temperature (15°C to 30°C).

Light

Protect from light.

Moisture

Protect from moisture.

SPECIAL HANDLING INSTRUCTIONS

Mylan-Buprenorphine/Naloxone should be kept in a safe place out of the sight and reach of children before, during and after use. Mylan-Buprenorphine/Naloxone should not be used in front of children, since they may copy these actions. Do not give to others.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Mylan-Buprenorphine/Naloxone is available as sublingual tablets:

2 mg / 0.5 mg tablets: A white to off-white, 0.2500” round, flat-faced, beveled edge tablet debossed with M inside a hexagon on one side of the tablet and 2-5 on the other side. Available in blister packages of 7 tablets and bottles of 100 tablets.

8 mg / 2 mg tablets: A white to off-white, 0.4062” round, flat-faced, beveled edge tablet debossed with M inside a hexagon on one side of the tablet and 8-2 on the other side. Available in blister packages of 7 tablets and bottles of 100 tablets.

Mylan-Buprenorphine/Naloxone Sublingual Tablets contain the following non-medicinal ingredients: aspartame, citric acid anhydrous, colloidal silicon dioxide, crospovidone, lactose monohydrate, lemon lime flavour, magnesium stearate, mannitol and sodium citrate.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Buprenorphine

Proper name: buprenorphine hydrochloride

Chemical name: 21-cyclopropyl-7a-[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6, 14- endo-ethano-6,7,8,14-tetrahydrooripavine hydrochloride

Molecular formula and molecular mass: C₂₉H₄₁NO₄•HCl; 504.10 g/mol

Structural formula:

Physicochemical properties:

Physical Form: White to off-white powder.

Solubility: Slightly soluble in methanol, slightly soluble in acetonitrile and slightly soluble in water.

pKa: pK1 = 8.5

pK2 = 10.0

pH: 4.0 to 6.0

Partition Coefficient: 2.826 ± 0.595

Specific Optical Rotation: Between -92° and -98°

Melting Point: About 272°, with decomposition

Naloxone

Proper name: naloxone hydrochloride dihydrate

Chemical name: 17-Allyl-4,5 a -epoxy-3, 14-dihydroxymorphinan-6-one hydrochloride dihydrate

Molecular formula and molecular mass: C19H21NO4•HCl•2H2O;

363.84 g/mol (anhydrous)

399.87 g/mol (dihydrate)

Structural formula:

2H20

Physicochemical properties:

Physical Form: White to slightly off-white powder.

Solubility: Freely soluble in methanol, very slightly soluble in acetonitrile and slightly soluble in water.

pKa: 6.71, 9.16 (naloxone)

pH: 2.5 to 3.5

Melting Point: 200 - 205^°C.

Partition Coefficient: 1.775 ± 0.564 (naloxone)

Specific Optical Rotation: Between -170° and -181°

CLINICAL TRIALS

Comparative Bioavailability Studies

A blinded, single dose, randomized, two-period, two-treatment, crossover study investigating the bioequivalence of Mylan-Buprenorphine/Naloxone (buprenorphine hydrochloride/naloxone hydrochloride dihydrate) 8 mg/2 mg sublingual tablets (Mylan Pharmaceuticals ULC) to Suboxone^TM 8 mg/2 mg sublingual tablets (Schering-Plough Canada Inc.) following administration of a single, oral 8 mg/2 mg (1 x 8 mg/2 mg) dose was performed in 46 healthy, adult subjects under fasting conditions.

A summary of the comparative bioavailability data is presented below.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* Buprenorphine hydrochloride/Naloxone hydrochloride dihydrate 8 mg/2 mg Sublingual Tablets, Mylan Pharmaceuticals ULC

^† Suboxone™ 8 mg/2 mg Sublingual Tablets, Schering-Plough Canada Inc., (Canada) were purchased in Canada

^§ For T_max Median (range) is presented

^€ For T_½ arithmetic mean (CV%) is presented

Efficacy and safety data of the combination of buprenorphine and naloxone (Studies CR96/013 + CR96/014)

This was a one-year multicenter, placebo-controlled study comprising a 4-week randomised double-blind comparison of buprenorphine/naloxone, buprenorphine and placebo tablets followed by a 48-week open-label safety study of buprenorphine/naloxone. In the first 4-week double-blind phase, 323 heroin-addicted subjects received either placebo, buprenorphine 16 mg/day, or combination treatment of 16 mg buprenorphine + 4 mg naloxone (combination tablet)

per day. For subjects randomized to 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. Subjects continued on 16 mg/day for four weeks. On day 3, subjects randomized to buprenorphine + naloxone were switched to the combination tablet. Subjects were seen daily in the clinic (Monday through Friday) for dosing and efficacy assessments. Subjects received one hour of individual counselling per week and a single session of HIV education. Outcome measures were % of urine samples negative for opioids and self-reported craving for opioids.

Study Results: The percentage of thrice-weekly urine samples that were negative for opiates was higher for subjects treated with buprenorphine (20.7%) or the combination tablet (17.8%) than for those who received placebo (both at p<0.001). In self-reported cravings both buprenorphine treated groups reported significantly less craving than placebo (p<0.001).

Comparative efficacy of buprenorphine and methadone (Study CR88/130)

This was a double-blind, double-dummy, parallel group, randomized study comparing buprenorphine ethanolic solution to methadone. One hundred sixty-two heroin dependent subjects age 21-50 years received sublingual buprenorphine (8 mg/day) or methadone (20 mg/day and 60 mg/day), during a 3-10-day induction phase, a 16-week maintenance phase and a 7-week detoxification phase. Buprenorphine was titrated to maintenance dose by day 3; methadone doses were titrated more gradually. Maintenance dosing continued through week 17, and then study drugs were tapered by approximately 70-80% per week over weeks 18-to-24, with placebo dosing for the last two weeks. Subjects received individual and/or group counselling weekly. Outcome measures were retention time in treatment, urine samples negative for opioids, and failure to maintain abstinence.

Study Results:

Based on retention in treatment and thrice-weekly urine samples negative for opiates, the effectiveness of buprenorphine was in the same range as methadone 60 mg, but superiority was not demonstrated.

DETAILED PHARMACOLOGY

Buprenorphine

Buprenorphine is a partial mu-opioid agonist and a kappa-opioid antagonist in tests involving bremazocine-induced diuresis. Activity at the mu-opioid receptor is the basis for its use in the treatment of opioid dependence.

Binding studies in both rat and guinea-pig brain demonstrate that buprenorphine has equal, high affinity for mu- and kappa-receptor sites with approximately 10-fold lower affinity for the delta subtype and no measurable affinity for the sigma opiate receptor. In vitro studies show low mu, very low delta, and undetectable kappa intrinsic activity.

Unlike some partial agonists, buprenorphine produces a biphasic dose-response curve in a variety of antinociceptive tests, in its effects on blood gases, on gastrointestinal motility, EEG, catalepsy, and on respiratory rate.

Buprenorphine demonstrates a slow rate of dissociation from its receptor in in vitro binding studies and isolated tissue tests. This very strong association of buprenorphine for the opioid receptor is reflected by the long duration of biological action. Buprenorphine shows a corresponding insensitivity to displacement by naloxone.

Direct dependence studies in monkey and rat were negative for both withdrawal induced by simple discontinuation of the treatment and by administration of naloxone. The low levels of physical withdrawal signs after chronic buprenorphine treatment is associated with its profile of very slow receptor kinetics and low mu intrinsic activity.

In self-administration studies in monkeys, buprenorphine was less reinforcing than other mixed agonist-antagonist analgesics, and significantly depressed the self-administration of opioids and cocaine.

Naloxone

Naloxone is an antagonist at mu, delta, and kappa-opioid receptors and produces opioid withdrawal effects in opioid-dependent subjects.

Naloxone in the combination tablet (buprenorphine/naloxone) has no clinically significant effect when administered by the sublingual route because of its poor sublingual absorption and short half-life relative to buprenorphine. IV administration of buprenorphine/naloxone combinations to opioid-dependent subjects, however, produced opioid-antagonist effects and withdrawal symptoms similar in magnitude to those produced by naloxone.

TOXICOLOGY

Pre-clinical and clinical doses or exposures are compared based on the clinical dose of 16 mg/4 mg buprenorphine/naloxone, or 16 mg buprenorphine. Preclinical doses or exposures are expressed as multiples of the corresponding clinical counterpart.

Buprenorphine/Naloxone

The toxicity profiles of buprenorphine and buprenorphine with naloxone in animals after a 28-day exposure period are similar in that no consistent target organ was identified, even at high oral doses.

No consistent pattern of undesirable effects was apparent in the subacute studies conducted, other than a sedative effect which is a direct consequence of the pharmacological activity of the test substance mixture.

Minimal to moderate hyperplasia of the bile duct with associated peribiliary fibrosis occurred in dogs following 52 weeks oral dosing of buprenorphine 75 mg/kg/day.

Fertility

Administration of buprenorphine/naloxone (4:1 ratio) to rats at 500 ppm or greater in the diet resulted in reduction in female fertility, whereas 100 ppm (estimated exposure approximately 5 times the human exposure from buprenorphine/naloxone 16 mg/4 mg based on plasma AUC) had no adverse effect on fertility in females.

Reproductive Toxicity

Reproduction studies with buprenorphine/naloxone indicated that embryo lethality occurred in rats in the presence of maternal toxicity at doses of 10 (oral) and 30 (intramuscular) mg/kg (buprenorphine:naloxone ratio of 1:1 at 10 mg/kg and 3:2 at 30 mg/kg). A no-effect level for this effect has not been established. 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 buprenorphine/naloxone; 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.

Mutagenicity

Buprenorphine/naloxone (4:1 ratio) was not mutagenic in a bacterial mutation assay (Ames test) using four strains of S. typhimurium and two strains of E. coli, in an in vitro cytogenetic assay in human lymphocytes or in an IV micronucleus test in rats.

Carcinogenicity

A carcinogenicity study of buprenorphine/naloxone (4:1 ratio) in rats at dietary levels yielding doses of approximately 7, 31, and 123 mg/kg/day (4-, 18-, and 44- fold clinical exposure) showed statistically significant increases in benign testicular Leydig cell adenomas in all dose groups. No other drug-related tumours were noted.

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