BUTRANS® (buprenorphine) transdermal system

BUTRANS® (buprenorphine) transdermal system

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BUTRANS® (buprenorphine) transdermal system

BUTRANS is a transdermal system providing systemic delivery of buprenorphine, a mu opioid partial agonist analgesic, continuously for 7 days. The chemical name of buprenorphine is 6,14- ethenomorphinan-7-methanol, 17-(cyclopropylmethyl)- -(1,1-dimethylethyl)-4, 5-epoxy-18, 19-dihydro-3-hydroxy-6-methoxy--methyl-, [5, 7, (S)].

The molecular weight of buprenorphine is 467.6; the empirical formula is C29H41NO4. Buprenorphine occurs as a white or almost white powder and is very slightly soluble in water, freely soluble in acetone, soluble in methanol and ether, and slightly soluble in cyclohexane. The pKa is 8.5 and the melting point is about 217C.

Indications

BUTRANS is a partial opioid agonist indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use

  • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve BUTRANS for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
  • BUTRANS is not indicated as an as-needed (prn) analgesic.

Mechanism of Action

Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappaopioid receptors, an agonist at delta-opioid receptors, and a partial agonist at ORL-1 (nociceptin) receptors. The contributions of these actions to its analgesic profile are unclear.

Effects on the Central Nervous System

Buprenorphine produces respiratory depression by direct action on brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Buprenorphine causes 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 origins may produce similar findings). Marked mydriasis rather than miosis may be seen with worsening hypoxia in overdose situations.

Dosage and administration

  • To be prescribed only by healthcare providers knowledgeable in use of potent opioids for management of chronic pain.
  • BUTRANS doses of 7.5, 10, 15, and 20 mcg/hour are only for use in patients who are opioid experienced and in whom tolerance to an opioid of comparable potency has been established. Patients who are opioid experienced are those receiving, for one week or longer, daily opioid doses up to 80 mg/day of oral morphine or an equal analgesic dose of another opioid.
  • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals
  • Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse.
  • For opioid-naïve patients, initiate treatment with a 5 mcg/hour patch.
  • Instruct patients to wear BUTRANS for 7 days and to wait a minimum of 3 weeks before applying to the same site.
  • Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with BUTRANS. Consider prescribing naloxone based on the patient’s risk factors for overdose.
  • Do not abruptly discontinue BUTRANS in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide

Contraindications

  • Significant respiratory depression
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
  • Known or suspected gastrointestinal obstruction, including paralytic ileus
  • Hypersensitivity to buprenorphine

Warnings and precautions

BUTRANS exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and monitor for these behaviors and conditions.

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products.

Serious, life-threatening or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients on proper administration of BUTRANS to reduce the risk.

Accidental exposure to BUTRANS, especially in children, can result in fatal overdose of buprenorphine.

Prolonged use of BUTRANS during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.

Patients with Chronic Pulmonary Disease: BUTRANS-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of BUTRANS

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients

Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of 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.

Severe Hypotension: BUTRANS may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics)

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness: In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), BUTRANS may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with BUTRANS.

Risks of Driving and Operating Machinery: BUTRANS may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of BUTRANS and know how they will react to the medication

Increased Risk of Seizures in Patients with Seizure Disorders: The buprenorphine in BUTRANS may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during BUTRANS therapy

Withdrawal: Do not abruptly discontinue buprenorphine in a patient physically dependent on opioids. When discontinuing BUTRANS in a physically dependent patient, gradually taper the dosage. Rapid tapering of buprenorphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain

Anaphylactic/Allergic Reactions: Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus.

Application Site Skin Reactions: In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred. Time of onset varies, ranging from days to months following the initiation of BUTRANS treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy.

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Adverse reactions

Most common adverse reactions (≥ 5%) include: nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.

Drug interactions

Benzodiazepines and Other Central Nervous System (CNS) Depressants: Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Inhibitors of CYP3A4: The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BUTRANS is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.

Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)

CYP3A4 Inducers: The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine, potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.

Examples: Rifampin, carbamazepine, phenytoin

Serotonergic Drugs: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs): MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). Examples: phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist Opioid Analgesics: May reduce the analgesic effect of BUTRANS and/or precipitate withdrawal symptoms. Examples: butorphanol, nalbuphine, pentazocine

Muscle Relaxants: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Diuretics: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Anticholinergic Drugs: The concomitant use of opioid analgesics, including buprenorphine, and anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Use in specific populations

Pregnancy: Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with BUTRANS in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly

Lactation: Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with BUTRANS.

Monitor infants exposed to BUTRANS through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of buprenorphine is stopped or when breast-feeding is stopped.

Infertility: Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible

Pediatric Use: The safety and efficacy of BUTRANS in patients under 18 years of age has not been established. BUTRANS has been evaluated in an open-label clinical trial in pediatric patients. However, definitive conclusions are not possible because of the small sample size.

Drug abuse and dependence

Controlled Substance: BUTRANS contains buprenorphine, a Schedule III controlled substance.

Abuse: BUTRANS contains buprenorphine, a Schedule III controlled substance with an abuse potential similar to other Schedule III opioids. BUTRANS can be abused and is subject to misuse, addiction and criminal diversion. The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

All patients treated with opioids, including BUTRANS, require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Dependence: Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Overdosage

Acute overdosage with BUTRANS is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations

Treatment of overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. However, naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10-35 mg/70 kg, may be of limited value in the management of buprenorphine overdose. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) has also been used.

In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

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