PAPAVERINE HCL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever the solution and container permit. Papaverine hydrochloride is a clear, colorless to pale-yellow solution.
Other Injectable Administration
Intra-Arterial Administration
NOTE: Papaverine hydrochloride is not labeled for intra-arterial administration.
-Dilute 30 mg papaverine plus heparin 1 unit/ml in a total volume of 250 ml of 0.9% or 0.45% sodium chloride (final concentration of papaverine 0.12 mg/ml).
-Do not add to Lactate Ringer's injection as precipitation will result.
-Infuse into a peripheral arterial catheter at a rate of 1 ml/hour.

Hyperpnea (increased depth of respiration), increases in heart rate, and slight increases in blood pressure have been reported during papaverine use. Drug causality is unknown.

Papaverine is reported to infrequently cause hepatitis that can rarely progress to cirrhosis in adult patients. Hepatotoxicity secondary to papaverine is believed to be immune mediated. In clinical studies that evaluated the safety and efficacy of papaverine for prolongation of peripheral arterial catheters patency in pediatric patients, hepatotoxicity was not observed. A group of neonates (n = 70) that received continuous infusions containing papaverine into the catheters had median values of conjugated bilirubin, AST, ALT and alkaline phosphatase that did not vary significantly from neonates that received placebo solution. If liver function tests become abnormal, or if hepatic hypersensitivity with associated GI symptoms, jaundice, or eosinophilia occurs, papaverine should be discontinued. Other GI adverse reactions reported during papaverine use in adults include abdominal pain, nausea, anorexia, constipation, and diarrhea.

Generalized malaise, diaphoresis, facial flushing, and excessive sedation (e.g., drowsiness) have been reported during papaverine use in adult populations. In a clinical study examining the safety and efficacy of papaverine for prolongation of peripheral arterial catheter patency in children 3 weeks to 18 years of age, no unexplained episodes of facial flushing or changes in mental status were observed. Vertigo and headache have also been observed during papaverine treatment in adults.

Severe, reversible thrombocytopenia related to intra-arterial papaverine has been described in one case report. On two separate occasions, an adult patient developed severe thrombocytopenia following injection of papaverine into the right internal carotid artery. Laboratory data supported the diagnosis of immune-mediated papaverine-induced thrombocytopenia.

Among critically ill neonates that received papaverine in arterial solutions for prevention of peripheral arterial catheter failure during a placebo controlled study, intraventricular hemorrhage (IVH) was reported; however, no significant difference in IVH incidence occurred between those who received papaverine or placebo. After the intervention, 19 of 70 patients in the papaverine group had IVH compared to 15 of 71 patients in the placebo group. Generally, papaverine should not be used in extremely premature neonates in the immediate period after birth when the neonate is at high risk of IVH, as papaverine-induced cerebral vasodilation may elevate IVH risk.

Rash (unspecified) has been reported during papaverine treatment. The exact incidence of the reaction is unknown. Observe patients for signs or symptoms of hypersensitivity during use.

Although the manufacturer indicates that papaverine should be administered with caution to patients with glaucoma, review of the literature suggests that cautious use is not warranted.

Papaverine is contraindicated in the presence of complete atrioventricular block (AV block). When conduction is depressed, the drug may produce transient ectopic rhythms of ventricular origin, either premature beats or paroxysmal tachycardia.

Description: Papaverine, a benzylisoquinoline alkaloid of opium, causes vascular smooth muscle relaxation. In pediatric patients, the drug is used for to prevent failure of peripheral arterial catheters. In a randomized, placebo-controlled trial in critically ill neonates, papaverine significantly prolonged arterial cathter functionality. Neonates were randomized to arterial catheter infusion solutions of 0.9% or 0.45% sodium chloride with 1 unit/ml heparin (n = 71 infants with 98 catheters), or the same solutions with papaverine 30 mg/250 ml added (n = 70 infants with 82 catheters). The median time to failure was 16.6 days with papaverine and 12 days with placebo (p = 0.023). Overall, the catheter failure rates were not significantly different between the groups. In a similar study of pediatric patients ages 3 weeks to 18 years, patients received placebo solution (0.9% or 0.45% sodium chloride with 1 unit/ml heparin) or identical solution with papaverine 30 mg/250 ml. The risk of catheter failure was lower in those that received papaverine (8 of 115 vs. 27 of 124 patients), and time until catheter failure was significantly longer in those who received papaverine. Papaverine is used off-label for prolongation of peripheral arterial catheter patency in pediatric patients as young as neonates.

For intravascular catheter occlusion prophylaxis* (prolongation of peripheral arterial catheter patency*):
Intra-Arterial dosage:
Neonates, Infants, Children, and Adolescents: 30 mg of papaverine added to 250 mL of arterial catheter infusion solution (0.9% or 0.45% sodium chloride with heparin 1 unit/mL) infused continuously at a rate of 1 mL/hour into a peripheral arterial catheter. Generally, avoid use in extremely premature neonates during the immediate period after birth when the risk of developing intracranial hemorrhage is highest.

Maximum Dosage Limits:
Safety and efficacy have not been established. Maximum dosage information is not available.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Papaverine acts by inhibiting phosphodiesterase in smooth muscle cells, which produces increased tissue levels of cyclic adenosine monophosphate and cyclic guanosine 3,5-monophosphate and subsequent relaxation of vascular smooth muscle. Calcium ion channels in cell membranes may also be blocked by papaverine, resulting in a reduction of release of calcium from the intracellular spaces. Papaverine has a spasmolytic effect on smooth muscle of the large blood vessels, particularly those of the peripheral arteries. This spasmolytic effect is unrelated to muscle innervation, and the muscle cell is still responsive to drugs and other stimuli which cause contraction.

For maintaining arterial catheter patency, it is theorized arterial vasoconstriction and subsequent thrombosis are responsible for the blockage of the catheter. The vasodilatory actions of papaverine may therefore decrease vasoconstriction and thus thrombosis of the arterial catheter.

Pharmacokinetics: In pediatric patients, papaverine is administered off-label intra-arterially to maintain arterial catheter patency. In other populations, the drug is administered intravenously, intramuscularly, and orally. A considerable amount of the drug localizes in the liver and fat deposits; the remainder of the drug is distributed throughout the body. Approximately 90% of the drug is bound to plasma protein. Papaverine is metabolized in the liver to inactive metabolites, which are excreted in the urine.