Sufentanil Citrate (Page 4 of 8)

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Epidural Use in Labor and Delivery

Epidural sufentanil was tested in 340 patients in two (one single-center and one multicenter) double-blind, parallel studies. Doses ranged from 10 to 15 mcg sufentanil and were delivered in a 10 mL volume of 0.125% bupivacaine with and without epinephrine 1:200,000. In all cases sufentanil was administered following a dose of local anesthetic to test proper catheter placement. Since epidural opioids and local anesthetics potentiate each other, these results may not reflect the dose or efficacy of epidural sufentanil by itself.

Individual doses of 10 to 15 mcg sufentanil plus bupivacaine 0.125% with epinephrine provided analgesia during the first stage of labor with a duration of 1 to 2 hours. Onset was rapid (within 10 minutes). Subsequent doses (equal dose) tended to have shorter duration. Analgesia was profound (complete pain relief) in 80% to 100% of patients and a 25% incidence of pruritus was observed. The duration of initial doses of sufentanil plus bupivacaine with epinephrine is approximately 95 minutes, and of subsequent doses, 70 minutes.

There are insufficient data to critically evaluate neonatal neuromuscular and adaptive capacity following recommended doses of maternally administered epidural sufentanil with bupivacaine. However, if larger than recommended doses are used for combined local and systemic analgesia, e.g., after administration of a single dose of 50 mcg epidural sufentanil during delivery, then impaired neonatal adaption to sound and light can be detected for 1 to 4 hours and if a dose of 80 mcg is used impaired neuromuscular coordination can be detected for more than 4 hours.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of sufentanil. 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 ingredients contained in Sufentanil Citrate Injection.

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been ‎reported with opioid therapy of any duration [see Warnings and Precautions ‎‎(5.7)]‎.

Hypoglycemia: Cases of hypoglycemia have been reported in patients ‎taking opioids. Most reports were in patients with at least one ‎predisposing risk factor (e.g., diabetes).‎

7 DRUG INTERACTIONS

Table 3 includes clinically significant drug interactions with Sufentanil Citrate Injection.

Table 3: Clinically Significant Drug Interactions with Sufentanil Citrate Injection

Inhibitors of CYP3A4

Clinical Impact:

The concomitant use of Sufentanil Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of sufentanil, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Sufentanil Citrate Injection is achieved [see Warnings and Precautions (5.4)].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease [see Clinical Pharmacology (12.3)] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil.

Intervention:

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

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

Examples:

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

CYP3A4 Inducers

Clinical Impact:

The concomitant use of Sufentanil Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of sufentanil [see Clinical Pharmacology (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil [see Warnings and Precautions (5.4)].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase [see Clinical Pharmacology (12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression.

Intervention:

If concomitant use is necessary, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Sufentanil Citrate Injection dosage reduction and monitor for signs of respiratory depression.

Examples:

Rifampin, carbamazepine, phenytoin

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Clinical Impact:

The concomitant use of Sufentanil Citrate Injection with CNS depressants my result in decreased pulmonary artery pressure and may cause hypotension. Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Sufentanil Citrate Injection. As postoperative analgesia, concomitant use of Sufentanil Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.2, 5.3)].

Intervention:

As postoperative analgesia, start with a lower dose of Sufentanil Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.8)].

Intervention:

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Sufentanil Citrate Injection 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase 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)].

Intervention:

The use of Sufentanil Citrate Injection 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 Sufentanil Citrate Injection and/or precipitate withdrawal symptoms.

Intervention:

Avoid concomitant use.

Examples:

butorphanol, nalbuphine, pentazocine, buprenorphine

Muscle Relaxants

Clinical Impact:

Sufentanil 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 Sufentanil Citrate Injection and/or the muscle relaxant as necessary.

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 Sufentanil Citrate Injection is used concomitantly with anticholinergic drugs.

Nitrous oxide

Clinical Impact:

Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Sufentanil Citrate Injection.

Intervention:

Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.

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