CASSIPA (buprenorphine and naloxone) sublingual film

CASSIPA (buprenorphine and naloxone) sublingual film

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CASSIPA (buprenorphine and naloxone) sublingual film

CASSIPA, 16 mg/4 mg, is a flexible, rectangular film with uniformly distributed orange color, imprinted with “16” in blue ink as a strength identifier (“16” may appear to be green in color). The film can be removed from the pouch as an intact piece. It contains buprenorphine HCl, a mu‐opioid receptor partial agonist and a kappa‐opioid receptor antagonist, and naloxone HCl dihydrate, an opioid receptor antagonist, at a ratio of 4:1 (ratio of free bases). It is intended for sublingual administration and is available as 16 mg buprenorphine with 4 mg naloxone. Each sublingual film also contains acesulfame potassium salt, ammonium hydroxide, anhydrous citric acid, butylated hydroxyanisole, butylated hydroxytoluene, FD&C Blue No. 1, FD&C Yellow #6, lemonlime flavor, maltitol, polyethylene oxide, povidone, shellac, and sodium phosphate, dibasic, anhydrous.

Chemically, buprenorphine HCl is (2S)‐2‐[17‐Cyclopropylmethyl‐4,5α‐epoxy‐3‐hydroxy‐6‐methoxy‐6α,14- ethano‐14α‐morphinan‐7α‐yl]‐3,3‐dimethylbutan‐2‐ol hydrochloride. M.F C29H41NO4 • HCl M.W. 504.10

Buprenorphine HCl is a white or off‐white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol, and practically insoluble in cyclohexane.

Chemically, naloxone HCl dihydrate is 17‐Allyl‐4,5 α‐epoxy‐3, 14‐dihydroxymorphinan‐6‐one hydrochloride dihydrate. M.F C19H21NO4 • HCl • 2H2O M.W. 399.87

Naloxone hydrochloride dihydrate is a white to slightly off‐white powder and is freely soluble in water, soluble in alcohol, and practically insoluble in toluene and ether.

Indications

CASSIPA film contains buprenorphine, a partial‐opioid agonist, and naloxone, an opioid antagonist, and is indicated for the maintenance treatment of opioid dependence.

CASSIPA should be used as part of a complete treatment plan that includes counseling and psychological support.

Mechanism of Action

CASSIPA contains buprenorphine and naloxone. Buprenorphine is a partial agonist at the mu‐opioid receptor and an antagonist at the kappa‐opioid receptor. Naloxone is a potent antagonist at mu‐opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists when administered parenterally.

Dosage and administration

  • Prescription use of this product is limited under the Drug Addiction Treatment Act.
  • Administer CASSIPA as a single daily dose.
  • Strongly consider prescribing naloxone at the time CASSIPA is initiated or renewed because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose.
  • CASSIPA should only be used after induction and stabilization of the patient, and the patient has been titrated to a dose of 16 mg buprenorphine using another marketed product.
  • Must be administered whole. Do not cut, chew, or swallow CASSIPA.
  • Place one film under the tongue, close to the base on the left or right side, and allow to completely dissolve.

Contraindications

CASSIPA is contraindicated in patients with a history of hypersensitive to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported.

Warnings and precautions

Addiction, Abuse, and Misuse: CASSIPA contains buprenorphine, a schedule III controlled substance that can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient’s level of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient follow‐up visits.

Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression: Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with CASSIPA. Use CASSIPA with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression).

Managing Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants: Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.

Unintentional Pediatric Exposure: Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it. Advise patients to store buprenorphine‐containing medications safely out of the sight and reach of children and to destroy any unused medication appropriately.

Neonatal Opioid Withdrawal Syndrome: 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 opioid withdrawal syndrome in adults, NOWS may be life‐threatening if not recognized and treated in the neonate.

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. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Risk of Opioid Withdrawal with Abrupt Discontinuation: 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. When discontinuing buprenorphine, gradually taper the dosage.

Risk of Hepatitis, Hepatic Events: 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 death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre‐existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role.

Hypersensitivity Reactions: Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in the post‐marketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of CASSIPA.

Risk of Overdose in Opioid Naïve Patients: There have been reported deaths of opioid-naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. CASSIPA is not appropriate as an analgesic and cannot be used in opioid-naïve patients.

Impairment of Ability to Drive or Operate Machinery: CASSIPA may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during dose adjustment. Patients should be cautioned about driving or operating hazardous machinery until they are reasonably certain that CASSIPA therapy does not adversely affect his or her ability to engage in such activities.

Orthostatic Hypotension: Like other opioids, CASSIPA may produce orthostatic hypotension in ambulatory patients.

Elevation of Cerebrospinal Fluid Pressure: Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

Elevation of Intracholedochal Pressure: Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

Adverse reactions

Adverse events commonly observed with the sublingual administration of buprenorphine and naloxone sublingual film were oral hypoesthesia, glossodynia, oral mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and peripheral edema.

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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, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

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

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 CASSIPA is achieved.

If concomitant use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

If dosage adjustments are needed, a different product should be used as the dose of CASSIPA cannot be adjusted. 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.

If concomitant use is necessary, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

If a CYP3A4 inducer is discontinued, consider dosage reduction and monitor for signs of respiratory depression.

If dosage adjustments are needed, a different product should be used as the dose of CASSIPA cannot be adjusted. 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.

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue CASSIPA if serotonin syndrome is suspected.

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).

The use of CASSIPA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid.

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

Monitor patients receiving muscle relaxants and CASSIPA for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine and/or the muscle relaxant as necessary.

If dosage adjustments are needed, a different product should be used as the dose of CASSIPA cannot be adjusted.

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

Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs: The 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 when CASSIPA is used concomitantly with anticholinergic drugs.

Use in specific populations

Pregnancy: The data on use of buprenorphine, one of the active ingredients in CASSIPA, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations.

Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.

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 dosage adjustments are needed, a different product should be used as the dose of CASSIPA cannot be adjusted.

Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with CASSIPA. Neonatal opioid withdrawal syndrome presents 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 neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly

Lactation: Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk and available data have not shown adverse reactions in breastfed infants. There are no data on the combination product buprenorphine/naloxone in breastfeeding, however oral absorption of naloxone is limited. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for buprenorphine and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of CASSIPA have not been established in pediatric patients. This product is not appropriate for the treatment of neonatal abstinence syndrome in neonates, because it contains naloxone, an opioid antagonist.

Drug abuse and dependence

Controlled Substance: CASSIPA contains buprenorphine, a Schedule III narcotic under the Controlled Substances Act.

Abuse: Buprenorphine, like morphine and other opioids, has the potential for being abused and is subject to criminal diversion. 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. Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Dependence: Buprenorphine is a partial agonist at the mu‐opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by moderate 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.

Overdosage

The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression, and death.

Treatment of Overdose

In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re‐establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated.

In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. The long duration of action of CASSIPA should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Insufficient duration of monitoring may put patients at risk.

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