Robinul Injectable :: Robins

DESCRIPTION

Robinul (glycopyrrolate) is a synthetic anticholinergic agent. Each 1 mL contains:
Glycopyrrolate, USP ................................. 0.2 mg  
Water for Injection, USP ................................ q.s.  
Benzyl Alcohol, NF (preservative) ............... 0.9%  
pH adjusted, when necessary, with hydrochloric acid and/or sodium hydroxide.

For Intramuscular or Intravenous administration.

Glycopyrrolate is a quaternary ammonium compound with the following chemical name:

3[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl pyrrolidinium bromide.

Unlike atropine, glycopyrrolate is completely ionized at physiological pH values.

Robinul Injectable is a clear, colorless, sterile liquid; pH 2.0-3.0.

CLINICAL PHARMACOLOGY

Glycopyrrolate, like other anticholinergic (antimuscarinic) agents, inhibits the action of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, the atrioventricular node, exocrine glands, and, to a limited degree, in the autonomic ganglia. Thus, it diminishes the volume and free acidity of gastric secretions and controls excessive pharyngeal, tracheal, and bronchial secretions.

Glycopyrrolate antagonizes muscarinic symptoms (e.g., bronchorrhea, bronchospasm, bradycardia, and intestinal hypermotility) induced by cholinergic drugs such as the anticholinesterases.

The highly polar quaternary ammonium group of glycopyrrolate limits its passage across lipid membranes, such as the blood-brain barrier, in contrast to atropine sulfate and scopolamine hydrobromide, which are non-polar tertiary amines which penetrate lipid barriers easily.

Peak effects occur approximately 30 to 45 minutes after intramuscular administration. The vagal blocking effects persist for 2 to 3 hours and the antisialagogue effects persist up to 7 hours, periods longer than for atropine. With intravenous injection, the onset of action is generally evident within one minute.

INDICATIONS AND USAGE

In Anesthesia: (glycopyrrolate) Injectable is indicated for use as a preoperative antimuscarinic to reduce salivary, tracheobronchial, and pharyngeal secretions; to reduce the volume and free acidity of gastric secretions; and, to block cardiac vagal inhibitory reflexes during induction of anesthesia and intubation. When indicated, Robinul Injectable may be used intraoperatively to counteract drug-induced or vagal traction reflexes with the associated arrhythmias. Glycopyrrolate protects against the peripheral muscarinic effects (e.g., bradycardia and excessive secretions) of cholinergic agents such as neostigmine and pyridostigmine given to reverse the neuromuscular blockade due to nondepolarizing muscle relaxants.

In Peptic Ulcer: use in adults as adjunctive therapy for the treatment of peptic ulcer when rapid anticholinergic effect is desired or when oral medication is not tolerated.

CONTRAINDICATIONS

Known hypersensitivity to glycopyrrolate.

Due to its benzyl alcohol content, Robinul Injectable should not be used in newborns (children less than 1 month of age).

In addition, in the management of peptic ulcer patients, because of the longer duration of therapy, Robinul Injectable may be contraindicated in patients with concurrent glaucoma; obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy); obstructive disease of the gastrointestinal tract (as in achalasia, pyloroduodenal stenosis, etc.); paralytic ileus, intestinal atony of the elderly or debilitated patient; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis; toxic megacolon complicating ulcerative colitis; myasthenia gravis.

WARNINGS

This drug should be used with great caution, if at all, in patients with glaucoma or asthma.

In the ambulatory patient. Robinul (glycopyrrolate) may produce drowsiness or blurred vision. The patient should be cautioned regarding activities requiring mental alertness such as operating a motor vehicle or other machinery or performing hazardous work while taking this drug.

In addition, in the presence of a high environmental temperature, heat prostration (fever and heat stroke due to decreased sweating) can occur with use of Robinul (glycopyrrolate).

Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance treatment with Robinul (glycopyrrolate) would be inappropriate and possibly harmful.

PRECAUTIONS

General

Investigate any tachycardia before giving glycopyrrolate since an increase in the heart rate may occur.

Use with caution in patients with: coronary artery disease; congestive heart failure; cardiac arrhythmias; hypertension; hyperthyroidism.

In managing ulcer patients, use Robinul with caution in the elderly and in all patients with autonomic neuropathy, hepatic or renal disease, ulcerative colitis or hiatal hernia, since anticholinergic drugs may aggravate these conditions.

With overdosage, a curare-like action may occur.

Drug Interactions

The intravenous administration of any anticholinergic in the presence of cyclopropane anesthesia can result in ventricular arrhythmias; therefore, caution should be observed if Robinul (glycopyrrolate) Injectable is used during cyclopropane anesthesia. If the drug is given in small incremental doses of 0.1 mg or less, the likelihood of producing ventricular arrhythmias is reduced.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. In the teratology studies, diminished rates of conception and of survival at weaning were observed in rats, in a dose-related manner. Studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate.

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits up to 1000 times the human dose and have revealed no teratogenic effects from glycopyrrolate. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Robinul is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children below the age of 12 years have not been established for the management of peptic ulcer.

ADVERSE REACTIONS

Anticholinergics produce certain effects, most of which are extensions of their pharmacologic actions. Adverse reactions to anticholinergics in general may include dry mouth; urinary hesitancy and retention; blurred vision due to mydriasis; increased ocular tension; tachycardia; palpitation; decreased sweating; loss of taste; headache; nervousness; drowsiness; weakness; dizziness; insomnia; nausea; vomiting; impotence; suppression of lactation; constipation; bloated feeling; severe allergic reaction or drug idiosyncrasies including anaphylaxis; urticaria and other dermal manifestations; some degree of mental confusion and/or excitement, especially in elderly persons.

Robinul is chemically a quaternary ammonium compound; hence, its passage across lipid membranes, such as the blood-brain barrier is limited in contrast to atropine sulfate and scopolamine hydrobromide. For this reason the occurrence of CNS related side effects is lower, in comparison to their incidence following administration of anticholinergics which are chemically tertiary amines that can cross this barrier readily.

OVERDOSAGE

To combat peripheral anticholinergic effects, a quaternary ammonium anticholinesterase such as neostigmine methylsulfate (which does not cross the blood-brain barrier) may be given intravenously in increments of 0.25 mg in adults. This dosage may be repeated every five to ten minutes until anticholinergic overactivity is reversed or up to a maximum of 2.5 mg. Proportionately smaller doses should be used in children. Indication for repetitive doses of neostigmine should be based on close monitoring of the decrease in heart rate and the return of bowel sounds.

In the unlikely event that CNS symptoms (excitement, restlessness, convulsions, psychotic behavior) occur, physostigmine (which does cross the blood-brain barrier) should be used. Physostigmine 0.5 to 2 mg should be slowly administered intravenously and repeated as necessary up to a total of 5 mg in adults. Proportionately smaller doses should be used in children.

Fever should be treated symptomatically. In the event of a curare-like effect on respiratory muscles, artificial respiration should be instituted and maintained until effective respiratory action returns.

DOSAGE AND ADMINISTRATION

Robinul (glycopyrrolate) Injectable may be administered intramuscularly, or intravenously, without dilution, in the following indications.

Adults: Preanesthetic Medication. The recommended dose of Robinul (glycopyrrolate) Injectable is 0.002 mg (0.01 mL) per pound of body weight by intramuscular injection, given 30 to 60 minutes prior to the anticipated time of induction of anesthesia or at the time the preanesthetic narcotic and/or sedative are administered.

Intraoperative Medication. Robinul (glycopyrrolate) Injectable may be used during surgery to counteract drug induced or vagal traction reflexes with the associated arrhythmias (e.g., bradycardia). It should be administered intravenously as single doses of 0.1 mg (0.5 mL) and repeated, as needed, at intervals of 2-3 minutes. The usual attempts should be made to determine the etiology of the arrhythmia, and the surgical or anesthetic manipulations necessary to correct parasympathetic imbalance should be performed.

Reversal of Neuromuscular Blockade. The recommended dose of Robinul (glycopyrrolate) Injectable is 0.2 mg (1.0 mL) for each 1.0 mg of neostigmine or 5.0 mg of pyridostigmine. In order to minimize the appearance of cardiac side effects, the drugs may be administered simultaneously by intravenous injection and may be mixed in the same syringe.

Children: (Read Contraindications). Preanesthetic Medication. The recommended dose of Robinul (glycopyrrolate) Injectable in children 1 month to 12 years of age is 0.002 mg (0.01 mL) per pound of body weight intramuscularly, given 30 to 60 minutes prior to the anticipated time of induction of anesthesia or at the time the preanesthetic narcotic and/or sedative are administered.

Children 1 month to 2 years of age may require up to 0.004 mg (0.02 mL) per pound of body weight.

Intraoperative Medication. Because of the long duration of action of Robinul (glycopyrrolate) if used as preanesthetic medication, additional Robinul (glycopyrrolate) Injectable for anticholinergic effect intraoperatively is rarely needed; in the event it is required the recommended pediatric dose is 0.002 mg (0.01 mL) per pound of body weight intravenously, not to exceed 0.1 mg (0.5 mL) in a single dose which may be repeated, as needed, at intervals of 2-3 minutes. The usual attempts should be made to determine the etiology of the arrhythmia, and the surgical or anesthetic manipulations necessary to correct parasympathetic imbalance should be performed.

Reversal of Neuromuscular Blockade. The recommended pediatric dose of Robinul (glycopyrrolate) Injectable is 0.2 mg (1.0 mL) for each 1.0 mg of neostigmine or 5.0 mg of pyridostigmine. In order to minimize the appearance of cardiac side effects, the drugs may be administered simultaneously by intravenous injection and may be mixed in the same syringe.

Adults:   Peptic Ulcer. The usual recommended dose of Robinul Injectable is 0.1 mg (0.5 mL) administered at 4-hour intervals, 3 or 4 times daily intravenously or intramuscularly. Where more profound effect is required, 0.2 mg (1.0 mL) may be given. Some patients may need only a single dose, and frequency of administration should be dictated by patient response up to a maximum of four times daily.

Robinul Injectable is not recommended for peptic ulcers in children under 12 years of age. (See Precautions .)

NOTE:   Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Admixture Compatibilities.  Robinul (glycopyrrolate) Injectable is compatible for mixing and injection with the following injectable dosage forms: 5% and 10% glucose in water or saline; atropine sulfate, USP; Antilirium® (physostigmine salicylate); Benadryl® (diphenhydramine HCl); codeine phosphate, USP; Emete-Con® (benzquinamide HCl); hydromorphone HCl, USP; Inapsine® (droperidol); Innovar® (droperidol and fentanyl citrate); Largon® (propiomazine HCl); Levo-Dromoran® (levorphanol tartrate); lidocaine, USP; Mepergan® (meperidine and promethazine HCls); meperidine HCl, USP; Mestinon® /Regonol® (pyridostigmine bromide); morphine sulfate, USP; Nisentil® (alphaprodine HCl); Nubain® (nalbuphine HCl); Numorphan® (oxymorphone HCl); Pantopon® (opium alkaloids HCls); procaine HCl, USP; promethazine HCl, USP; Prostigmin® (neostigmine methylsulfate, USP); scopolamine HBr, USP; Sparine® (promazine HCl); Stadol® (butorphanol tartrate); Sublimaze® (fentanyl citrate); Talwin® (pentazocine lactate); Tigan® (trimethobenzamide HCl); Vesprin® (triflupromazine HCl); and Vistaril® (hydroxyzine HCl). Robinul Injectable may be administered via the tubing of a running infusion of physiological saline or lactated Ringer' solution.

Since the stability of glycopyrrolate is questionable above a pH of 6.0, do not   combine Robinul Injectable in the same syringe with Brevital® (methohexital Na); Chloromycetin® (chloramphenicol Na succinate); Dramamine® (dimenhydrinate); Nembutal® (pentobarbital Na); Pentothal® (thiopental Na); Seconal® (secobarbital Na); sodium bicarbonate (Abbott); or Valium® (diazepam). A gas will evolve or a precipitate may form. Mixing with Decadron® (dexamethasone Na phosphate) or a buffered solution of lactated Ringer' solution will result in a pH higher than 6.0. Mixing chlorpromazine HCl, USP, or Compazine® (prochlorperazine) with other agents in a syringe is not recommended by the manufacturer, although the mixture with Robinul Injectable is physically compatible.

HOW SUPPLIED

Robinul (glycopyrrolate) Injectable, 0.2 mg/mL, is available in 1 mL single dose vials packaged in 25's (NDC 0031-7890-11), 2 mL single dose vials packaged in 25's (NDC 0031-7890-95), 5 mL multiple dose vials packaged in 25's (NDC 0031-7890-06), and 20 mL (NDC 0031-7890-83) multiple dose vials.

Store at controlled room temperature, between 20°C and 25°C (68°F and 77°F).

Manufactured by:

Pharmaceutical Division

A. H. Robins Company

Richmond, VA 23220

CI 4932-1  Issued April 25, 1997



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