GLYRX-PF

6 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. Most common adverse reactions are related to anticholinergic pharmacology and may include xerostomia (dry mouth); urinary hesitancy and retention; blurred vision and photophobia due to mydriasis (dilation of the pupil); cycloplegia; increased ocular tension; tachycardia; bradycardia; palpitation; and decreased sweating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Exela Pharma Sciences, LLC at 1-888-451-4321 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS 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. • Known hypersensitivity to glycopyrrolate or any of its inactive ingredients. ( 4 ) • Peptic ulcer patients with glaucoma; obstructive uropathy; obstructive disease of the gastrointestinal tract; 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. ( 4 )

11 DESCRIPTION GLYRX ® -PF is a synthetic anticholinergic agent. It is intended for intramuscular or intravenous administration. Each 1 mL of GLYRX ® -PF 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] α-cyclopentylmandelate. The molecular formula is C 19 H 28 BrNO 3 and the molecular weight is 398.34. Glycopyrrolate 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 (log 10 P = -1.52) at ambient room temperature (24°C). Structure

2 DOSAGE AND ADMINISTRATION GLYRX ® -PF may be administered intramuscularly (IM), or intravenously (IV), with or without dilution, in the following indications. ( 2.1 ): Adults ( 2.2 ) Preanesthetic Medication: 0.004 mg/kg IM, given 30 to 60 minutes prior to the anticipated time of induction of anesthesia Intraoperative Medication: single doses of 0.1 mg IV and repeated, as needed, at intervals of 2 to 3 minutes Reversal of Neuromuscular Blockade: 0.2 mg for each 1 mg of neostigmine or 5 mg of pyridostigmine Peptic Ulcer: 0.1 mg IV or IM at 4-hour intervals, 3 or 4 times daily Pediatric patients ( 2.3 ) Preanesthetic Medication: 0.004 mg/kg IM, given 30 to 60 minutes prior to the anticipated time of induction of anesthesia. Patients under 2 years of age may require up to 0.009 mg/kg Intraoperative Medication: 0.004 mg/kg IV, not to exceed 0.1 mg in a single dose and repeated, as needed, at intervals of 2 to 3 minutes Reversal of Neuromuscular Blockade: 0.2 mg for each 1 mg of neostigmine or 5 mg of pyridostigmine Peptic Ulcer: GLYRX ® -PF is not indicated for the treatment of peptic ulcer in pediatric patients 2.1 General Dosage and Administration Information • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. • GLYRX ® -PF may be administered intramuscularly or intravenously, with or without dilution. 2.2 Dosing in Adults Preanesthetic Medication The recommended dose of GLYRX ® -PF is 0.004 mg/kg 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 GLYRX ® -PF may be used during surgery to counteract drug-induced or vagal reflexes and their associated arrhythmias (e.g., bradycardia). It should be administered intravenously as single doses of 0.1 mg and repeated, as needed, at intervals of 2 to 3 minutes. Attempt to determine the etiology of the arrhythmia, and perform the surgical or anesthetic manipulations necessary to correct parasympathetic imbalance. Reversal of Neuromuscular Blockade The recommended dose of GLYRX ® -PF is 0.2 mg for each 1 mg of neostigmine or 5 mg of pyridostigmine. In order to minimize cardiac side effects, the drugs may be administered simultaneously by intravenous injection and may be mixed in the same syringe. Peptic Ulcer The usual recommended dose of GLYRX ® -PF is 0.1 mg administered at 4-hour intervals, 3 or 4 times daily, intravenously or intramuscularly. Where more profound effect is required, 0.2 mg may be given. Some patients may need only a single dose. Frequency of administration should be dictated by patient response up to a maximum of four times daily. 2.3 Dosing in Pediatric Patients Preanesthetic Medication The recommended dose of GLYRX ® -PF in pediatric patients is 0.004 mg/kg 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. Patients under 2 years of age, may require up to 0.009 mg/kg. Intraoperative Medication Because of the long duration of action of GLYRX ® -PF if used as preanesthetic medication, additional GLYRX ® -PF for anticholinergic effect intraoperatively is rarely needed; in the event it is required, the recommended pediatric dose is 0.004 mg/kg intravenously, not to exceed 0.1 mg in a single dose, which may be repeated, as needed, at intervals of 2 to 3 minutes. Attempt to determine the etiology of the arrhythmia, and perform the surgical or anesthetic manipulations necessary to correct parasympathetic imbalance. Reversal of Neuromuscular Blockade The recommended pediatric dose of GLYRX ® -PF is 0.2 mg for each 1 mg of neostigmine or 5 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. Peptic Ulcer GLYRX ® -PF is not indicated for the treatment of peptic ulcer in pediatric patients. 2.4 Preparation and Handling Diluent Compatibilities Dextrose 5% and 10% in water, or saline, dextrose 5% in sodium chloride 0.45%, sodium chloride 0.9%, and Ringer’s Injection. Diluent Incompatibilities Lactated Ringer’s solution. Admixture Compatibilities Physical Compatibility This list does not constitute an endorsement of the clinical utility or safety of co-administration of glycopyrrolate with these drugs. GLYRX ® -PF is compatible for mixing and injection with the following injectable dosage forms: atropine sulfate, USP; physostigmine salicylate; diphenhydramine HCl; codeine phosphate, USP; benz-quinamide HCl; hydromorphone HCl, USP; droperidol; levorphanol tartrate; lidocaine, USP; meperidine HCl, USP; pyridostigmine bromide; morphine sulfate, USP; nalbuphine HCl; oxymorphone HCl; procaine HCl, USP; promethazine HCl, USP; neostigmine methylsulfate, USP; scopolamine HBr, USP; butorphanol tartrate; fentanyl citrate; trimethobenzamide HCl; and hydroxyzine HCl. GLYRX ® -PF may be administered via the tubing of a running infusion of normal saline. Admixture Incompatibilities Physical Incompatibility Because the stability of glycopyrrolate is questionable above a pH of 6.0 do not combine GLYRX ® -PF in the same syringe with methohexital Na, chloramphenicol Na succinate, dimenhydrinate, pentobarbital Na, thiopental Na, secobarbital Na, sodium bicarbonate, diazepam, dexamethasone Na phosphate, or pentazocine lactate. These mixtures will result in a pH higher than 6.0 and may result in gas production or precipitation. 2.5 Instructions for Use of Prefilled Syringe 1. Perform visual inspection on the syringe by verifying: • Absence of syringe damage • Absence of external particles • Absence of internal particles • Proper drug color • Drug name • Drug strength • Fill volume • Route of administration • Expiration date to be sure the drug has not expired 2. Do not remove the tamper evident seal. Push plunger rod slightly in to break the stopper lose while tip cap is still on 3. Remove tip cap and tamper evident seal by twisting off. (See Figure 1): Figure 1. 4. Discard the tip cap. 5. Expel air bubble. 6. Adjust dose into sterile material (if applicable). 7. Connect the syringe to an appropriate intravenous connection. • Before injection, ensure that the syringe is securely attached to the needle or needleless luer access device (NLAD). 8. Depress plunger rod to deliver medication. Ensure that pressure is maintained on the plunger rod during the entire administration. 9. Remove syringe from NLAD (if applicable) and discard into appropriate receptacle. • To prevent needle stick injuries, do not recap needle when needle is connected to syringe. NOTES: All steps must be done sequentially • Do not re-sterilize syringe • Do not use this product on a sterile field • Do not introduce any other fluid into the syringe at any time • This product is for single dose only Figure 1

1 INDICATIONS AND USAGE GLYRX ® -PF is indicated: in anesthesia (all ages) • for reduction of salivary, tracheobronchial, and pharyngeal secretions, reduction of volume and acidity of gastric secretions, and blockade of cardiac inhibitory reflexes during induction of anesthesia and intubation, • intraoperatively to counteract surgically or drug-induced or vagal reflex-associated arrhythmias, and • for protection against peripheral muscarinic effects of cholinergic agents such as neostigmine and pyridostigmine given to reverse the neuromuscular blockade due to non-depolarizing agents. in peptic ulcer (adults) • as adjunctive therapy for the treatment of peptic ulcer when rapid anticholinergic effect is desired or when oral medication is not tolerated. GLYRX ® -PF is an anticholinergic indicated: in anesthesia (adult and pediatric patients) • for reduction of airway or gastric secretions, and volume and acidity of gastric secretions, and blockade of cardiac inhibitory reflexes during induction of anesthesia and intubation, • intraoperatively to counteract surgically or drug-induced or vagal reflex-associated arrhythmias, and • for protection against peripheral muscarinic effects of cholinergic agents. ( 1 ) in peptic ulcer (adults) • as adjunctive therapy for the treatment of peptic ulcer when rapid anticholinergic effect is desired or oral medication is not tolerated. ( 1 )

5.1 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).

10 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 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.

7 DRUG INTERACTIONS 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. Other anticholinergics or drugs with anticholinergic activity : May intensify the antimuscarinic effects and result in an increase in anticholinergic side effects. ( 7 ) Potassium Chloride in a Wax Matrix : May increase severity of potassium chloride-induced gastrointestinal lesions. ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 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. 12.2 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. 12.3 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 t 1/2 V ss CL T max C max AUC (hr) (L/kg) (L/kg/hr) (min) (µg/L) (µg/L•hr) (6 µg/kg IV) 0.83 ± 0.27 0.42 ± 0.22 0.54 ± 0.14 – – 8.64 ± 1.49 0-8 hr (8 µg/kg IM) – – – 27.48 ± 6.12 3.47 ± 1.48 6.64 ± 2.33 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.

12.1 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.

12.2 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.

12.3 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 t 1/2 V ss CL T max C max AUC (hr) (L/kg) (L/kg/hr) (min) (µg/L) (µg/L•hr) (6 µg/kg IV) 0.83 ± 0.27 0.42 ± 0.22 0.54 ± 0.14 – – 8.64 ± 1.49 0-8 hr (8 µg/kg IM) – – – 27.48 ± 6.12 3.47 ± 1.48 6.64 ± 2.33 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.

20180801

4

3 DOSAGE FORMS AND STRENGTHS GLYRX ® -PF (glycopyrrolate injection) is a clear, colorless, solution for injection available as 0.2 mg/mL and 0.4 mg/2 mL (0.2 mg/mL) single-dose vials and as a 0.6 mg/3 mL and 1 mg/5 mL (0.2 mg/mL) single-dose prefilled syringe. Injection: 0.2 mg/mL and 0.4 mg/2 mL (0.2 mg/mL) single-dose vial and 0.6 mg/3 mL and 1 mg/5 mL (0.2 mg/mL) single-dose prefilled syringe. ( 3 )

GLYRX-PF glycopyrrolate GLYCOPYRROLATE GLYCOPYRRONIUM WATER SODIUM CHLORIDE HYDROCHLORIC ACID SODIUM HYDROXIDE GLYRX-PF glycopyrrolate GLYCOPYRROLATE GLYCOPYRRONIUM WATER SODIUM CHLORIDE HYDROCHLORIC ACID SODIUM HYDROXIDE GLYRX-PF glycopyrrolate GLYCOPYRROLATE GLYCOPYRRONIUM WATER SODIUM CHLORIDE HYDROCHLORIC ACID SODIUM HYDROXIDE GLYRX-PF glycopyrrolate GLYCOPYRROLATE GLYCOPYRRONIUM WATER SODIUM CHLORIDE HYDROCHLORIC ACID SODIUM HYDROXIDE

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis and 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.

NDA210997

GLYRX-PF

glycopyrrolate

51754-6001

HUMAN PRESCRIPTION DRUG

INTRAMUSCULAR,INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL- 3 mL Syringe Label NDC 51754-6013-1 Rx only GLYRX ® -PF Glycopyrrolate Injection 0.6 mg/3 mL (0.2 mg/mL) 3 mL Single Dose prefilled syringe. Discard Unused Portion. For IM or IV Use. Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature 3 mL Syring Label

5.3 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.

8.5 Geriatric Use Clinical Studies of GLYRX ® -PF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other therapy.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established for the management of peptic ulcer. Dysrhythmias associated with the use of glycopyrrolate intravenously as a premedicant or during anesthesia have been observed in pediatric patients. Infants, patients with Down’s syndrome, and pediatric patients with spastic paralysis or brain damage may experience an increased response to anticholinergics, thus increasing the potential for side effects. A paradoxical reaction characterized by hyperexcitability may occur in pediatric patients receiving large doses of anticholinergics including GLYRX ® -PF. Infants and young children are especially susceptible to the toxic effects of anticholinergics.

8.1 Pregnancy Risk Summary Limited data available with glycopyrrolate use during pregnancy have not identified a drug-associated risk of birth defects and miscarriage, however, most of the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of Cesarean-section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores (see Data). In animal reproduction studies in pregnant rats and rabbits administered glycopyrrolate orally (rats) and intramuscularly (rabbits) during the period of organogenesis, no teratogenic effects were seen at 640-times and 10-times the maximum recommended human dose (MRHD) of 1 mg (on a mg/m 2 basis), respectively (see Data) . The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15−20%, respectively. Data Human Data Published, randomized, controlled trials over several decades, which compared the use of glycopyrrolate to another antimuscarinic agent in pregnant women during Cesarean section, have not identified adverse maternal or infant outcomes. In normal doses (0.004 mg/kg), glycopyrrolate does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. Concentrations of glycopyrrolate in umbilical venous and arterial blood and in the amniotic fluid are low after intramuscular administration to parturients. Therefore, glycopyrrolate does not appear to penetrate through the placental barrier in significant amounts. There are no studies on the safety of glycopyrrolate exposure during the period of organogenesis, and therefore, it is not possible to draw any conclusions on the risk of birth defects following exposure to glycopyrrolate during pregnancy. In addition, there are no data on the risk of miscarriage following fetal exposure to glycopyrrolate. Animal Data Reproduction studies with glycopyrrolate were performed in rats at a dietary dose of approximately 65 mg/kg/day (exposure was approximately 640 times the maximum recommended daily human dose of 1 mg on a mg/m 2 basis) and rabbits at intramuscular doses of up to 0.5 mg/kg/day (exposure was approximately 10 times the maximum recommended daily human dose on a mg/m 2 basis). These studies produced no teratogenic effects to the fetus. A preclinical study on reproductive performance of rats given glycopyrrolate resulted in a decreased rate of conception and survival at weaning.

8 USE IN SPECIFIC POPULATIONS Pediatric Use : Infants, patients with Down’s Syndrome, and pediatric patients with spastic paralysis or brain damage may experience an increased response to anticholinergics, thus increasing the potential for side effects. Large doses may cause hyperexcitability. ( 8.4 ). 8.1 Pregnancy Risk Summary Limited data available with glycopyrrolate use during pregnancy have not identified a drug-associated risk of birth defects and miscarriage, however, most of the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of Cesarean-section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores (see Data). In animal reproduction studies in pregnant rats and rabbits administered glycopyrrolate orally (rats) and intramuscularly (rabbits) during the period of organogenesis, no teratogenic effects were seen at 640-times and 10-times the maximum recommended human dose (MRHD) of 1 mg (on a mg/m 2 basis), respectively (see Data) . The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15−20%, respectively. Data Human Data Published, randomized, controlled trials over several decades, which compared the use of glycopyrrolate to another antimuscarinic agent in pregnant women during Cesarean section, have not identified adverse maternal or infant outcomes. In normal doses (0.004 mg/kg), glycopyrrolate does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. Concentrations of glycopyrrolate in umbilical venous and arterial blood and in the amniotic fluid are low after intramuscular administration to parturients. Therefore, glycopyrrolate does not appear to penetrate through the placental barrier in significant amounts. There are no studies on the safety of glycopyrrolate exposure during the period of organogenesis, and therefore, it is not possible to draw any conclusions on the risk of birth defects following exposure to glycopyrrolate during pregnancy. In addition, there are no data on the risk of miscarriage following fetal exposure to glycopyrrolate. Animal Data Reproduction studies with glycopyrrolate were performed in rats at a dietary dose of approximately 65 mg/kg/day (exposure was approximately 640 times the maximum recommended daily human dose of 1 mg on a mg/m 2 basis) and rabbits at intramuscular doses of up to 0.5 mg/kg/day (exposure was approximately 10 times the maximum recommended daily human dose on a mg/m 2 basis). These studies produced no teratogenic effects to the fetus. A preclinical study on reproductive performance of rats given glycopyrrolate resulted in a decreased rate of conception and survival at weaning. 8.2 Lactation Risk Summary There are no data on the presence of glycopyrrolate in either human milk or animal milk, the effects on the breastfed infant, or the effects on milk production. As with other anticholinergics, glycopyrrolate may cause suppression of lactation [see Adverse Reactions ( 6 )] . The developmental and health benefits of breast feeding should be considered along with the mother’s clinical need for Glycopyrrolate Injection and any potential adverse effects on the breastfed child from Glycopyrrolate Injection or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established for the management of peptic ulcer. Dysrhythmias associated with the use of glycopyrrolate intravenously as a premedicant or during anesthesia have been observed in pediatric patients. Infants, patients with Down’s syndrome, and pediatric patients with spastic paralysis or brain damage may experience an increased response to anticholinergics, thus increasing the potential for side effects. A paradoxical reaction characterized by hyperexcitability may occur in pediatric patients receiving large doses of anticholinergics including GLYRX ® -PF. Infants and young children are especially susceptible to the toxic effects of anticholinergics. 8.5 Geriatric Use Clinical Studies of GLYRX ® -PF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other therapy. 8.6 Renal Impairment Renal elimination of glycopyrrolate may be severely impaired in patients with renal failure. Dosage adjustments may be necessary [see Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED, STORAGE AND HANDLING GLYRX ® -PF (glycopyrrolate injection) is available in: 0.2 mg/mL single-dose vials packaged in 25s (NDC 51754-6000-4) 0.4 mg/2 mL (0.2 mg/mL) single-dose vials packaged in 25s (NDC 51754-6001-4) 0.6 mg/3 mL (0.2 mg/mL) single-dose prefilled disposable syringes packaged in 10s (NDC 51754-6013-3) 1 mg/5 mL (0.2 mg/mL) single-dose prefilled disposable syringes packaged in 10s (NDC 51754-6015-3) Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature].

5.2 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.