2.1 Important Dosage and Administration Instructions

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with belladonna and opium suppositories and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with belladonna and opium suppositories [see Warnings and Precautions (5.2), Patient Counseling Information (17)].

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions (5.1, 5.2, 5.4)].

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

2.3 Dosing

One belladonna and opium suppository rectally once or twice daily, not to exceed four doses daily or as recommended by the physician. Moisten finger and suppository with water before inserting. Absorption is dependent on body hydration and not on body temperature. Not recommended for use in children 12 years of age and under.

Conversion from Other Opioids to Belladonna and Opium Suppositories

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of belladonna and opium suppositories. It is safer to underestimate a patient’s 24-hour belladonna and opium suppositories dosage than to overestimate the 24-hour belladonna and opium suppositories dosage and manage an adverse reaction due to overdose.

Conversion from Belladonna and Opium suppositories to Extended-Release Opioid

The relative bioavailability of belladonna and opium suppositories compared to extended-release opioid is unknown, so conversion to extended-release drug product must be accompanied by close observation for signs of excessive sedation and respiratory depression.

2.4 Maintenance of Therapy

Continually reevaluate patients receiving belladonna and opium suppositories to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1)]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the belladonna and opium suppositories dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

2.5 Safe Reduction or Discontinuation of Belladonna and Opium Suppositories

Do not abruptly discontinue belladonna and opium suppositories in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

When a decision has been made to decrease the dose or discontinue therapy in an opioid dependent patient taking belladonna and opium suppositories, there are a variety of factors that should be considered, including the dose of belladonna and opium suppositories the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist.

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on belladonna and opium suppositories who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, monitor patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

When managing patients taking opioid analgesics, particularly those who have been treated for a long duration and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)].

5.1 Addiction, Abuse, and Misuse

Belladonna and opium suppositories contains opium, a Schedule II controlled substance. As an opioid, belladonna and opium suppositories expose users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed belladonna and opium suppositories. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing belladonna and opium suppositories, and monitor all patients receiving belladonna and opium suppositories for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as belladonna and opium suppositories, but use in such patients necessitates intensive counseling about the risks and proper use of belladonna and opium suppositories along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing belladonna and opium suppositories. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of belladonna and opium suppositories, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of belladonna and opium suppositories.

To reduce the risk of respiratory depression, proper dosing of belladonna and opium suppositories is essential [see Dosage and Administration (2.3)]. Overestimating the belladonna and opium suppositories dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental exposure of even one dose of belladonna and opium suppositories, especially by children, can result in respiratory depression and death due to an overdose of opium.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with belladonna and opium suppositories. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Warnings and Precautions (5.2, 5.6), Patient Counseling Information (17)].

5.3 Neonatal Opioid Withdrawal Syndrome

Prolonged use of belladonna and opium suppositories during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

5.4 Risks from Concomitant Use with Benzodiazepines or Other Central Nervous System Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of belladonna and opium suppositories with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, 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 analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when belladonna and opium suppositories are 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 (7) and Patient Counseling Information (17)].

5.5 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of belladonna and opium suppositories in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: Belladonna and opium suppositories-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 belladonna and opium suppositories [see Warnings and Precautions (5.2)].

Elderly, Cachetic, 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 [see Warnings and Precautions (5.2)].

Monitor such patients closely, particularly when initiating and titrating belladonna and opium suppositories and when belladonna and opium suppositories is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.6 Interactions with Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of opioids, including respiratory depression, coma, and confusion. Belladonna and opium suppositories should not be used in patients taking MAOIs or within 14 days of stopping such treatment.

5.7 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.

5.8 Severe Hypotension

Belladonna and opium suppositories may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is 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) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of belladonna and opium suppositories. In patients with circulatory shock, belladonna and opium suppositories may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of belladonna and opium suppositories in patients with circulatory shock.

5.9 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), belladonna and opium suppositories 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 belladonna and opium suppositories.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of belladonna and opium suppositories in patients with impaired consciousness or coma.

5.10 Risks of Use in Patients with Gastrointestinal Conditions

Belladonna and opium suppositories are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The opium in belladonna and opium suppositories may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.11 Increased Risk of Seizures in Patients with Seizure Disorders

The opium in belladonna and opium suppositories may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during belladonna and opium suppositories therapy.

5.12 Withdrawal

Do not abruptly discontinue belladonna and opium suppositories in a patient physically dependent on opioids. When discontinuing belladonna and opium suppositories in a physically dependent patient, gradually taper the dosage. Rapid tapering of opium in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)].

Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including belladonna and opium suppositories. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

5.13 Risks of Driving and Operating Machinery

Belladonna and opium suppositories may impair the mental or 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 belladonna and opium suppositories and know how they will react to the medication.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of opioids. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

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

Anaphylaxis: Anaphylaxis has been reported with products containing opioids.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.

8.1 Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. There are no available data with belladonna and opium suppositories in pregnant women to inform a drug associated risk for major birth defects and miscarriage.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

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. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].

Belladonna refers to plant alkaloids that contain anticholinergic agents such as atropine. Atropine used in human pregnancies has not been associated with birth defects or adverse fetal effects although the drug readily crosses the placenta. Use during pregnancy may increase risk of respiratory abnormalities, hypospadias, and eye or ear malformations but causal relationship is unclear. The Collaborative Perinatal Project found no relationship between first trimester use of atropine and birth defects in the offspring but found an increase in birth defects in general in the offspring of pregnancies where the mother had taken belladonna. There was no relationship to any particular syndrome of anomalies. A statistically significant (although weak) association was discovered between congenital anomalies and maternal use of belladonna. A study was conducted based on the infants of 554 women who took belladonna during the first four months of pregnancy. The study was conducted in the Collaborative Perinatal Project and showed that belladonna is unlikely to cause minor congenital abnormalities. The estimated maximum risk is most likely less than 3% if maternal belladonna is used early in pregnancy.1

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Belladonna and opium suppositories is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including belladonna and opium suppositories, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

8.2 Lactation

Risk Summary

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for belladonna and opium suppositories and any potential adverse effects on the breastfed infant from belladonna and opium suppositories or from the underlying maternal condition.

Clinical Considerations

Infants exposed to belladonna and opium suppositories through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

8.3 Females and Males of Reproductive Potential

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.

8.4 Pediatric Use

The safety and effectiveness of belladonna and opium suppositories in pediatric patients have not been established.

8.5 Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to belladonna and opium. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of belladonna and opium suppositories slowly in geriatric patients [see Warnings and Precautions (5.2)].

9.1 Controlled Substance

Belladonna and opium suppositories contains opium, a Schedule II controlled substance.

9.2 Abuse

Belladonna and opium suppositories contains opium, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. Belladonna and opium suppositories can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

All patients treated with opioids 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.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.

Belladonna and opium suppositories, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Belladonna and Opium Suppositories

Belladonna and opium suppositories are for rectal use only. Abuse of belladonna and opium suppositories poses a risk of overdose and death. The risk is increased with concurrent abuse of belladonna and opium suppositories with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.3 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 results 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), mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Belladonna and opium suppositories should not be abruptly discontinued [see Dosage and Administration (2.4)]. If belladonna and opium suppositories is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Do not abruptly discontinue belladonna and opium suppositories in a patient physically dependent on opioids. Rapid tapering of belladonna and opium suppositories in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing belladonna and opium suppositories, gradually taper the dosage using a patient-specific plan that considers the following: the dose of belladonna and opium suppositories the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5), Warnings and Precautions (5.12)].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

12.1 Mechanism of Action

Belladonna/opium rectal suppository is a combination narcotic analgesic/antispasmodic agent. The belladonna extract component of the rectal suppository provides the active alkaloids atropine and scopolamine, while the opium component provides primarily morphine (among more than 20 alkaloids). The atropine alkaloid is parasympatholytic, exerting antispasmodic activity by relaxation of smooth muscle that is stimulated by the parasympathetic nervous system. The atropine alkaloid is also the dl isomer of l-hyoscyamine and exerts the same pharmacologic activity; however, it exerts about one-half the activity peripherally as l-hyoscyamine. Atropine activity also counteracts morphine induced smooth muscle spasm without affecting the analgesia. The morphine alkaloid of opium exerts analgesic activity by increasing the pain threshold and decreasing the sensitivity to pain. The oxidative dealkylated nor-metabolites of morphine begin the analgesic process. Additionally, the side effect of euphoria may contribute to sense of pain relief.

12.2 Pharmacodynamics

Through its parasympatholytic action, atropine (belladonna) relaxes smooth muscle resulting from parasympathetic stimulation. It is the dl isomer of l-hyoscyamine and therefore exhibits the same clinical effects. It is, however, approximately one-half as active peripherally as l-hyoscyamine, the latter being the major active plant alkaloid. The dl isomer atropine is formed during the process of isolation of the belladonna extract.1

Morphine, the major active principle of powdered opium, is responsible for the action of powdered opium although the other alkaloids present also contribute to it. The sedative and analgesic action of morphine, the effect desired by inclusion in belladonna and opium suppositories of powdered opium, are thought to be due to the depressant effect on the cerebral cortex, hypothalamus and medullary centers. In large doses, the opiates and their analogs also exhibit synaptic conduction in the spinothalamic tracts, depress the function of the reticular formation, the lemniscus and the thalamic relays, and inhibit spinal synaptic reflexes: but these inhibitor actions should not be elicited with therapeutic doses of the drug. Moderate doses of powdered opium should not alter the electroencephalogram.

The action of morphine consists mainly of a descending depression of the central nervous system. It exerts its analgesic action by increasing the pain threshold or the magnitude of stimulus required to evoke pain and by dulling the sensibility or reaction to pain. In addition to its action in abolishing pain, morphine induces a sense of well-being (euphoria) facilitating certain mental processes while retarding others.

12.3 Pharmacokinetics

Upon absorption of morphine, oxidative dealkylation to produce nor-compounds appears to be the first step in the reaction sequence which imparts analgesia. Morphine is conjugated in the liver to form the 3-glucuronide which passes into the bile and is reabsorbed and excreted in the urine. The atropine effect of the belladonna extract serves to eliminate morphine induced smooth muscle spasm without affecting the sedative analgesic action of powdered opium.1