GLYRX-PF

Description for GLYRX-PF

GLYRX-PF is a synthetic anticholinergic agent. It is intended for intramuscular or intravenous administration. Each 1 mL contains 0.2 mg of glycopyrrolate, water for injection, sodium chloride as a tonicity agent, and hydrochloric acid or sodium hydroxide as pH adjusters. GLYRX-PF is preservative free.

Glycopyrrolate is a quaternary ammonium salt with the following chemical name: (RS)-[3-(SR)Hydroxy- 1,1-dimethylpyrrolidinium bromide] a-cyclopentylmandelate The molecular formula is C₁₉H₂₈BrNO₃ and the molecular weight is 398.33.

Its structural formula is as follows:

Glycopyrrolate occurs as a white, odorless, crystalline powder. It is soluble in water and alcohol, and practically insoluble in chloroform and ether. It is completely ionized at physiological pH values. GLYRX-PF is a clear, colorless, sterile liquid with a pH of 2.0 – 3.0. The partition coefficient of Glycopyrrolate in n-octanol/water system is 0.304 (log₁₀ P = -1.52) at ambient room temperature (24°C).

ADVERSE REACTIONS

The following adverse reactions were identified in clinical studies or postmarketing reports. Because some of these reactions were 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.

Adverse reactions to anticholinergics include xerostomia (dry mouth); urinary hesitancy and retention; blurred vision and photophobia due to mydriasis (dilation of the pupil); cycloplegia; 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 reactions including anaphylactic/anaphylactoid reactions; hypersensitivity; urticaria, pruritus, dry skin, and other dermal manifestations; some degree of mental confusion and/or excitement, especially in elderly persons.

The following adverse reactions have been reported from post-marketing experience with glycopyrrolate: malignant hyperthermia; cardiac arrhythmias (including bradycardia, ventricular tachycardia, ventricular fibrillation); cardiac arrest; hypertension; hypotension; seizures; and respiratory arrest. Post-marketing reports have included cases of heart block and QTc interval prolongation associated with the combined use of glycopyrrolate and an anticholinesterase. Injection site reactions including pruritus, edema, erythema, and pain have also been reported.

Drug Interactions for GLYRX-PF

The concurrent use of GLYRX^®-PF with other anticholinergics or medications with anticholinergic activity, such as phenothiazines, antiparkinson drugs, or tricyclic antidepressants, may intensify the antimuscarinic effects and result in an increase in anticholinergic side effects.

Concomitant administration of GLYRX^®-PF and potassium chloride in a wax matrix may increase the severity of potassium chloride-induced gastrointestinal lesions as a result of a slower gastrointestinal transit time.

Warnings for GLYRX-PF

Included as part of the PRECAUTIONS section.

Precautions for GLYRX-PF

Precipitation of Acute Glaucoma

Glycopyrrolate may cause mydriasis and increase intraocular pressure in patients with glaucoma. Advise patients with glaucoma to promptly seek medical care in the event that they experience symptoms of acute angle closure glaucoma (pain and reddening of the eyes, accompanied by dilated pupils).

Drowsiness or Blurred Vision

GLYRX^®-PF may cause drowsiness or blurred vision. Warn patients not to participate in activities requiring mental alertness, such as operating a motor vehicle or other machinery, or performing hazardous work, until these issues resolve.

Heat Prostration

In the presence of fever, high environmental temperature, and/or during physical exercise, heat prostration can occur with use of anticholinergic agents including GLYRX^®-PF (due to decreased sweating), particularly in children and the elderly. Advise patients to avoid exertion and high environmental temperature after receiving GLYRX^®-PF.

Intestinal Obstruction

Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance treatment with GLYRX^®-PF is inappropriate and possibly harmful. Avoid use in patients with these conditions.

Tachycardia

Investigate any tachycardia before giving GLYRX^®-PF because an increase in the heart rate may occur. Use with caution in patients with coronary artery disease, congestive heart failure, cardiac arrhythmias, hypertension, or hyperthyroidism.

Risk of Use in Patients with Renal Impairment

Renal elimination of glycopyrrolate may be severely impaired in patients with renal failure. Dosage adjustments may be necessary in this population [see Clinical Pharmacology (12.3)].

Autonomic Neuropathy, Hepatic Disease, Ulcerative Colitis, Prostatic Hypertrophy, or Hiatal Hernia

Use GLYRX^®-PF with caution in the elderly and in all patients with autonomic neuropathy, hepatic disease, ulcerative colitis, prostatic hypertrophy, or hiatal hernia, because anticholinergic drugs may aggravate these conditions. Consider dose reduction and closely monitor the elderly and patients with autonomic neuropathy, hepatic disease, ulcerative colitis, prostatic hypertrophy, or hiatal hernia.

Delayed Gastric Emptying/Gastric Stasis

The use of anticholinergic drugs, including GLYRX^®-PF, in the treatment of peptic ulcer may produce a delay in gastric emptying/gastric stasis. Monitor patients for symptoms such as vomiting, dyspepsia, early satiety, abdominal distention, and increased abdominal pain. Discontinue GLYRX^®-PF treatment if these symptoms develop or worsen on treatment.

Light Sensitivity

Patients may experience sensitivity of the eyes to light. Advise patients to protect their eyes from light after receiving GLYRX^®-PF.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Mutagenesis

Studies to evaluate the mutagenic potential of glycopyrrolate have not been conducted.

Impairment of Fertility

In reproduction studies in rats, dietary administration of glycopyrrolate resulted in diminished rates of conception in a dose-related manner. Other studies in dogs suggest that this may be due to diminished seminal secretion which is evident at high doses of glycopyrrolate.

OVERDOSES

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 pediatric patients. Indication for repetitive doses of neostigmine should be based on close monitoring of the decrease in heart rate and the return of bowel sounds.

If CNS symptoms (e.g., excitement, restlessness, convulsions, psychotic behavior) occur, physostigmine (which does cross the blood–brain barrier) may 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 pediatric patients.

To combat hypotension, administer IV fluids and/or pressor agents along with supportive care. Fever should be treated symptomatically.

Following overdosage, a curare-like action may occur, i.e., neuromuscular blockade leading to muscular weakness and possible paralysis. In the event of a curare-like effect on respiratory muscles, artificial respiration should be instituted and maintained until effective respiratory action returns.

Contraindications for GLYRX-PF

GLYRX^®-PF is contraindicated in:

• patients with known hypersensitivity to glycopyrrolate or any of its inactive ingredients.
• peptic ulcer patients with the following concurrent conditions: 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.

Clinical Pharmacology for GLYRX-PF

Mechanism Of Action

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.

Pharmacodynamics

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 highly non-polar tertiary amines which penetrate lipid barriers easily. 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. With intravenous injection, the onset of action is generally evident within one minute. Following intramuscular administration, the onset of action is noted in 15 to 30 minutes, with peak effects occurring within approximately 30 to 45 minutes. The vagal blocking effects persist for 2 to 3 hours and the antisialagogue effects persist up to 7 hours, periods longer than for atropine.

Pharmacokinetics

The following pharmacokinetic information and conclusions were obtained from published studies that used nonspecific assay methods.

Distribution

The mean volume of distribution of glycopyrrolate was estimated to be 0.42 ± 0.22 L/kg.

Elimination

Metabolism

The in vivo metabolism of glycopyrrolate in humans has not been studied.

Excretion

The mean clearance and mean t_1/2 values were reported to be 0.54 ± 0.14 L/kg/hr and 0.83 ± 0.27 hr, respectively post IV administration. After IV administration of a 0.2 mg radiolabeled glycopyrrolate, 85% of dose recovered was recovered in urine 48 hours post dose and some of the radioactivity was also recovered in bile. After IM administration of glycopyrrolate to adults, the mean t_1/2 value is reported to be between 0.55 to 1.25 hrs. Over 80% of IM dose administered was recovered in urine and the bile as unchanged drug and half the IM dose is excreted within 3 hrs. The following table summarizes the mean and standard deviation of pharmacokinetic parameters from a study.

Group	t1/2 (hr)	Vss (L/kg)	CL (L/kg/hr)	Tmax (min)	Cmax (µg/L)	AUC (µg/L•hr)
(6 µg/kg IV)	0.83 ± 0.27	0.42 ± 0.22	0.54 ± 0.14	–	–	8.64 ± 1.491
(8 µg/kg IM)	–	–	–	27.48 ± 6.12	3.47 ± 1.48	6.64 ± 2.331

Specific Populations

Pediatric Patients:

Following IV administration (5 μg/kg glycopyrrolate) to infants and children, the mean t_1/2 values were reported to be between 21.6 and 130.0 minutes and between 19.2 and 99.2 minutes, respectively.

Patients with Renal Impairment:

In one study Glycopyrrolate was administered IV in uremic patients undergoing renal transplantation. The mean elimination half-life was significantly longer (46.8 minutes) than in healthy patients (18.6 minutes). The mean area-under- the-concentration-time curve (10.6 hr-μg/L), mean plasma clearance (0.43 L/hr/kg), and mean 3-hour urine excretion (0.7%) for Glycopyrrolate were also significantly different than those of controls (3.73 hr-μg/L, 1.14 L/hr/kg, and 50%, respectively). These results suggest that the elimination of glycopyrrolate is severely impaired in patients with renal failure.

Patient Information for GLYRX-PF

Drowsiness or Blurred Vision: Inform patients that GLYRX^®-PF may cause drowsiness or blurred vision. Warn patients not to operate a motor vehicle or other machinery or perform hazardous work until these issues resolve [see Warnings and Precautions (5.2)].

Heat Prostration: Inform patients that in the presence of fever, high environmental temperature and/or during physical exercise, heat prostration can occur with use of anticholinergic agents, including GLYRX^®-PF (due to decreased sweating), particularly in children and the elderly. Advise patients to avoid exertion and high environmental temperature after receiving GLYRX^®-PF [see Warnings and Precautions (5.3)].

Light Sensitivity: Advise patients that glycopyrrolate injection may cause sensitivity of the eyes to light and to protect their eyes from light after receiving GLYRX^®-PF [see Warnings and Precautions (5.9)].

Drug Interactions: Inform patients that GLYRX^®-PF may interact with other drugs. Advise patients to report to their healthcare provider the use of any other medication [see Drug Interactions (7)].

Manufactured and Distributed by:

Exela Pharma Sciences,
LLC Lenoir, NC 28645