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 analgesic 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. 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 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 (5.7), Drug Interactions (7) ]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [ see Warnings and Precautions (5.9) ]
• 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)
• 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. (5.6)
• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Morphine Sulfate Oral Solution in patients with circulatory shock. (5.7)
• 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. (5.8)

5.1Addiction, Abuse, and Misuse Belladonna

and opium suppositories contains opium, a Schedule II controlled substance. As an opioid, belladonna and opium suppositories exposes 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. 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.

Table 1 includes clinically significant drug interactions with belladonna and opium suppositories. Table 1: Clinically Significant Drug Interactions with Belladonna and Opium Suppositories Alcohol, 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 [ see Warnings and Precautions (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 (MAOI) 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.

8.1Pregnancy 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. 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.

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 (5.6) ]
• Severe Hypotension [ see Warnings and Precautions (5.7) ]
• Gastrointestinal Adverse Reactions [ see Warnings and Precautions (5.9) ]
• 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 Perrigo at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.2Postmarketing 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