Atropa Belladonna and Opium

Belladonna and opium suppositories are indicated for the management of ureteral spasm pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses [see Warnings and Precautions ( 5.1 )] , reserve belladonna and opium suppositories for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

• Have not been tolerated, or are not expected to be tolerated,
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia Belladonna and opium suppositories are an opioid agonist indicated for the management of ureteral spasm pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use ( 1 ) Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve belladonna and opium suppositories for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products):
• Have not been tolerated, or are not expected to be tolerated,
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia

Belladonna and Opium Suppositories are available in two strengths.

• Belladonna 16.2 mg and opium 30 mg
• Belladonna 16.2 mg and opium 60 mg Suppositories:
• Belladonna 16.2 mg and opium 30 mg
• Belladonna 16.2 mg and opium 60 mg

Belladonna and opium suppositories are contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions ( 5.2 )]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.5 )]
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7 )]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.10 )]
• Hypersensitivity to opium or belladonna [see Adverse Events ( 6 )]
• Glaucoma 2
• Severe hepatic or renal disease 2
• Narcotic idiosyncrasies 2
• Convulsive disorders 2
• Acute alcoholism 2
• Delirium tremens 2
• Premature labor 2
• Significant respiratory depression. ( 4 )
• Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 )
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days. ( 4 )
• Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 )
• Known hypersensitivity to opium or belladonna. ( 4 )

These preparations are not recommended for use in children.

• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. ( 5.5 )
• Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.7 )
• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of belladonna and opium suppositories in patients with circulatory shock. ( 5.8 )
• Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of belladonna and opium suppositories in patients with impaired consciousness or coma. ( 5.9 )

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 (CO 2 ) 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. […]

Belladonna may cause drowsiness, dry mouth, urinary retention, photophobia, rapid pulse, dizziness and blurred vision 7 . Opium usage may result in constipation, nausea or vomiting. Pruritis and urticaria may occasionally occur. Hypersensitivity to opium or belladonna may occur. The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )]
• Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.3 )]
• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions ( 5.4 )]
• Adrenal Insufficiency [see Warnings and Precautions ( 5.7 )]
• Severe Hypotension [see Warnings and Precautions ( 5.8 )]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.10 )]
• Seizures [see Warnings and Precautions ( 5.11 )]
• Withdrawal [see Warnings and Precautions ( 5.12 )] Most common adverse reactions are drowsiness, dry mouth, urinary retention, photophobia, rapid pulse, dizziness and blurred vision, constipation, nausea and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

Table 1 includes clinically significant drug interactions with belladonna and opium suppositories. Table 1: Clinically Significant Drug Interactions with Belladonna and Opium Suppositories Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: 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. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.4 )] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue belladonna and opium suppositories 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 effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2 )] If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Intervention: The use of belladonna and opium suppositories is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of belladonna and opium suppositories and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Opium may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of belladonna and opium suppositories and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.4 )] . Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when belladonna and opium suppositories are used concomitantly with anticholinergic drugs.

• Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue belladonna and opium suppositories if serotonin syndrome is suspected. ( 7 )
• Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of opium. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 )
• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with belladonna and opium suppositories because they may reduce analgesic effect of belladonna and opium suppositories or precipitate withdrawal symptoms. ( 7 )

Pregnancy : May cause fetal harm. ( 8.1 )

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 )] .

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.