Papaverine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PAPAVERINE (PAPAVERINE)

Composition:

Active substance: papaverine;

1 ml of solution contains papaverine hydrochloride 20 mg;

Excipients: disodium edetate, methionine, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, slightly yellowish liquid.

Pharmacotherapeutic group. Drugs used in functional gastrointestinal disorders. Papaverine and its derivatives. ATC code A03A D01.

Pharmacological properties.

Pharmacodynamics.

Papaverine is an alkaloid found in opium. Papaverine is a myotropic spasmolytic agent. It reduces muscle tone, decreases contractile activity of smooth muscles, and thereby exerts vasodilatory and spasmolytic effects. Papaverine is an inhibitor of the enzyme phosphodiesterase, which leads to intracellular accumulation of cyclic 3’,5’-adenosine monophosphate (cAMP). Accumulation of cAMP results in impaired contractility of smooth muscles and their relaxation in spastic conditions. The effect of papaverine on the central nervous system is weak; only at higher doses does it exhibit some sedative effect.

Pharmacokinetics.

After parenteral administration, the drug rapidly forms stable complexes with serum albumins. It readily penetrates histohematological barriers. It is metabolized in the liver. Approximately 60 % is excreted as conjugates, mainly phenolic conjugates with glucuronic acid, and only in insignificant amounts in unchanged form. The elimination half-life is 0.5–2 hours.

Clinical characteristics.

Indications.

• Spasms of smooth muscles of abdominal organs (pylorospasm, irritable bowel syndrome, cholecystitis, biliary colic attacks);
• spasms of urinary tract, renal colic;
• cerebral vessel spasm;
• peripheral vessel spasm (endarteritis).

Contraindications.

Hypersensitivity to the components of the drug, arterial hypotension, atrioventricular conduction disturbances, coma, respiratory depression, concomitant use of monoamine oxidase inhibitors; glaucoma, hepatic insufficiency, bronchoobstructive syndrome, patient age over 75 years (risk of hyperthermia).

Interaction with other medicinal products and other types of interactions.

The spasmolytic effect of papaverine is enhanced by barbiturates, diphenhydramine (dimedrol), metamizole (analgin), diclofenac. The hypotensive effect is enhanced when used concomitantly with antihypertensive agents of other groups, as well as with tricyclic antidepressants, procainamide, reserpine, and quinidine. Papaverine may reduce the antiparkinsonian effect of levodopa and the hypotensive effect of methyldopa. When used simultaneously with alprostadil for intracavernous administration, there is a risk of priapism development. Phentolamine potentiates the effect of papaverine on the corpora cavernosa of the penis when administered together.

When used concomitantly with cardiac glycosides, a pronounced enhancement of myocardial contractile function occurs due to decreased total peripheral vascular resistance. When used together with procainamide, enhancement of the hypotensive effect is possible.

A possible reduction in the tonic effect of anticholinesterase agents on smooth muscle under the influence of papaverine hydrochloride may occur.

A possible reduction in the spasmolytic activity of papaverine hydrochloride under the influence of morphine may occur. However, papaverine hydrochloride is used together with morphine hydrochloride to reduce the spasmogenic effect of the latter, and with promedol – in cases of pain associated with spasm of smooth musculature.

There are reports of hepatitis development with concomitant use of papaverine and furadantin.

When combining reserpine preparations with papaverine hydrochloride, antihypertensive action is enhanced.

When combined with antidepressants, enhancement of the hypotensive effect is possible.

When used simultaneously, papaverine hydrochloride potentiates the effect of alcohol.

In patients who smoke, papaverine metabolism is accelerated, and its plasma concentration and pharmacokinetic effects are reduced.

Pharmaceutically compatible with dibazole.

Special precautions.

The drug should be administered with caution and in doses lower than the average therapeutic dose:

• to elderly and debilitated patients;
• to patients with head trauma;
• to patients with chronic renal insufficiency;
• to patients with supraventricular tachycardia, severe heart failure with signs of decompensation;
• in adrenal insufficiency, hypothyroidism, benign prostatic hyperplasia, shock states.

The drug should be administered intravenously very slowly and under monitoring of arterial pressure, heart rate, and with ECG monitoring.

Intravenous injections of the drug should be administered with caution in patients with stenosing coronary atherosclerosis.

Hyperthermia may occur in elderly patients.

Smoking reduces the effectiveness of the drug.

Alcohol should not be consumed during treatment with this drug.

This medicinal product contains less than 1 mmol/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

The safety and efficacy of the drug during pregnancy or breastfeeding have not been established. Breastfeeding should be discontinued for the duration of treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

During treatment with this drug, patients should refrain from driving or operating complex machinery.

Administration and Dosage

The drug is administered subcutaneously, intramuscularly, and intravenously.

Subcutaneously and intramuscularly, adults and children aged 14 years and older should receive 0.5–2 mL (10–40 mg) of a 2% solution. For intravenous administration, the drug must be administered very slowly at a rate of 3–5 mL/min, after dissolving 1 mL of 2% papaverine hydrochloride solution (20 mg) in 10–20 mL of 0.9% sodium chloride solution. For elderly patients, the initial single dose should not exceed 10 mg (0.5 mL of 2% solution). Intravenous administration is the most effective.

Maximum doses for adults:

• Subcutaneous or intramuscular: single dose – 100 mg (5 mL of 2% solution), daily dose – 300 mg (15 mL of 2% solution)
• Intravenous: single dose – 20 mg (1 mL of 2% solution), daily dose – 120 mg (6 mL of 2% solution)

Children aged 1 to 14 years should receive the drug 2–3 times daily. The single dose is 0.7–1 mg/kg of body weight.

Maximum daily dose for children (regardless of administration route):

• Age 1–2 years: 20 mg (1 mL of 2% solution)
• Age 3–4 years: 30 mg (1.5 mL of 2% solution)
• Age 5–6 years: 40 mg (2 mL of 2% solution)
• Age 7–9 years: 60 mg (3 mL of 2% solution)
• Age 10–14 years: 100 mg (5 mL of 2% solution)

Children. The drug may be administered to children aged 1 year and older.

Overdose.

Symptoms: visual disturbances, diplopia, weakness, dry mouth, constipation, facial flushing, hyperventilation, nystagmus, ataxia, tachycardia, arterial hypotension, asystole, ventricular flutter, collapse. When high doses are used or the drug is administered rapidly intravenously, arrhythmias or complete atrioventricular block may develop. When used in very high doses, papaverine may produce moderate sedative effects.

Treatment: Discontinue the drug. Symptomatic treatment is recommended. There is no specific antidote.

The drug is completely removed from the blood during hemodialysis.

Adverse reactions.

Central and peripheral nervous system: drowsiness, increased sweating, weakness, headache, dizziness.

Sensory organs: visual disturbances, diplopia.

Gastrointestinal tract: anorexia, nausea, constipation, dry mouth, diarrhea.

Liver and biliary system: jaundice, liver function disorders, increased activity of liver transaminases.

Cardiovascular system: arrhythmia, tachycardia, arterial hypotension, partial or complete atrioventricular block, asystole, ventricular extrasystoles, ventricular fibrillation, ventricular flutter, collapse.

Blood system: eosinophilia.

Respiratory system: apnea.

Skin, subcutaneous tissue and immune system: hypersensitivity reactions, including respiratory tract involvement, anaphylactic shock, hyperemia of the skin of the upper trunk, face and hands; pruritus; skin rash, urticaria.

Allergic reactions: hypersensitivity reactions.

Other: reactions at the injection site, including thrombosis at the injection site.

Incompatibility.

Pharmaceutically compatible with dibazol, chemically incompatible with sodium caffeine benzoate. Use only the recommended solvent.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Packaging. 2 ml in ampoules. 10 ampoules per partitioned box; or 5 ampoules in a single-sided blister, 2 blisters per box; or 100 ampoules per partitioned box.

Prescription status.

Prescription only.

Manufacturer.

Private Joint-Stock Company "Lekhym-Kharkiv".

Manufacturer's address and location of business activity.

36 Severina Pototskoho Street, Kharkiv, Kharkiv region, 61115, Ukraine.