5.1 Blurred Vision

Miotics, including pilocarpine hydrochloride ophthalmic solution, may cause accommodative spasm. Patients should be advised not to drive or operate machinery if vision is not clear (e.g., blurred vision).

In addition, patients may experience temporary dim or dark vision with miotics, including pilocarpine hydrochloride ophthalmic solution. Patients should be advised to exercise caution in night driving and other hazardous activities in poor illumination.

5.2 Risk of Retinal Detachment

Rare cases of retinal detachment and retinal tear have been reported with miotics, including pilocarpine hydrochloride ophthalmic solution.

Individuals with pre-existing retinal disease are at increased risk. Therefore, examination of the retina is advised in all patients prior to the initiation of therapy.

Patients should be advised to seek immediate medical care with sudden onset of flashing lights, floaters or vision loss.

5.3 Iritis

Pilocarpine hydrochloride ophthalmic solution is not recommended to be used when iritis is present because adhesions (synechiae) may form between the iris and the lens.

5.4 Use with Contact Lenses

Contact lens wearers should be advised to remove their lenses prior to the instillation of pilocarpine hydrochloride ophthalmic solution and to wait 10 minutes after dosing before reinserting their contact lenses.

5.5 Potential for Eye Injury or Contamination

To prevent eye injury or contamination, care should be taken to avoid touching the dispensing bottle to the eye or to any other surface.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Pilocarpine hydrochloride ophthalmic solution dosed once daily was evaluated in 375 participants with presbyopia in two randomized, double-masked, vehicle-controlled studies (GEMINI 1 and GEMINI 2) of 30 days duration. The most common adverse reactions reported in > 5% of participants were headache and conjunctival hyperemia. Ocular adverse reactions reported in 1% to 5% of participants were blurred vision, eye pain, visual impairment, eye irritation and increased lacrimation.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of pilocarpine hydrochloride ophthalmic solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to pilocarpine hydrochloride ophthalmic solution exposure.

Eye disorders: vitreous detachment, vitreomacular traction, retinal tear, retinal detachment.

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies of pilocarpine hydrochloride ophthalmic solution administration in pregnant women to inform a drug-associated risk. Oral administration of pilocarpine to pregnant rats throughout organogenesis and lactation did not produce adverse effects at clinically relevant doses.

Data

Human Data

No adequate and well-controlled trials of pilocarpine hydrochloride ophthalmic solution have been conducted in pregnant women. In a retrospective case series of 15 women with glaucoma, 4 patients used ophthalmic pilocarpine either pre-pregnancy, during pregnancy or postpartum. There were no adverse effects observed in patients or in their infants.

Animal Data

In embryofetal development studies, oral administration of pilocarpine to pregnant rats throughout organogenesis produced maternal toxicity, skeletal anomalies and reduction in fetal body weight at 90 mg/kg/day (approximately 485-fold higher than the maximum human ophthalmic dose [MHOD] of 0.015 mg/kg/day, on a mg/m2 basis).

In a peri-/postnatal study in rats, oral administration of pilocarpine during late gestation through lactation increased stillbirths at a dose of 36 mg/kg/day (approximately 195-fold higher than the MHOD). Decreased neonatal survival and reduced mean body weight of pups were observed at ≥ 18 mg/kg/day (approximately 100 times the maximum human ophthalmic dose of pilocarpine hydrochloride ophthalmic solution).

8.2 Lactation

Risk Summary

There is no information regarding the presence of pilocarpine in human milk, the effects on the breastfed infants, or the effects on milk production to inform risk of pilocarpine hydrochloride ophthalmic solution to an infant during lactation.

Pilocarpine and/or its metabolites are excreted in the milk of lactating rats. Systemic levels of pilocarpine following topical ocular administration are low [see Clinical Pharmacology (12.3)] and it is not known whether measurable levels of pilocarpine would be present in maternal milk following topical ocular administration.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pilocarpine hydrochloride ophthalmic solution and any potential adverse effects on the breastfed child from pilocarpine hydrochloride ophthalmic solution.

Data

Animal Data

Following a single oral administration of 14C-pilocarpine to lactating rats, the radioactivity concentrations in milk were similar to those in plasma.

8.4 Pediatric Use

Presbyopia does not occur in the pediatric population.

8.5 Geriatric Use

Clinical studies of pilocarpine hydrochloride ophthalmic solution did not include participants aged 65 and over to determine whether they respond differently from younger participants. Other reported clinical experience with ophthalmic pilocarpine solutions have not identified overall differences in safety between elderly and younger participants.

12.1 Mechanism of Action

Pilocarpine hydrochloride is a cholinergic muscarinic agonist which activates muscarinic receptors located at smooth muscles such as the iris sphincter muscle and ciliary muscle. Pilocarpine hydrochloride contracts the iris sphincter muscle, constricting the pupil to improve near and intermediate visual acuity while maintaining some pupillary response to light. Pilocarpine hydrochloride also contracts the ciliary muscle and may shift the eye to a more myopic state.

12.3 Pharmacokinetics

Systemic exposure to pilocarpine was evaluated in 22 participants with presbyopia who were administered 1 drop of pilocarpine hydrochloride ophthalmic solution in each eye once daily for 30 days (GEMINI 1). The mean (SD) Cmax and AUC values from time 0 to last measurable concentration over 10-hour period post-last dose on Day 30 were 1.95 (0.98) ng/mL and 4.14 (2.16) ng·hr/mL, respectively. The median Tmax value on Day 30 was 0.3 hours post-dose with a range from 0.2 hours to 0.5 hours post-dose.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Pilocarpine did not induce tumors in mice at any dosage level studied (up to 30 mg/kg/day; approximately 80-times the MHOD). In rats, an oral dose of 18 mg/kg/day (approximately 100 times the MHOD), resulted in a statistically significant increase in the incidence of benign pheochromocytomas in both male and female rats and a statistically significant increase in the incidence of hepatocellular adenomas in female rats.

Mutagenesis

Pilocarpine did not show any potential to cause genetic toxicity in a series of studies that included:

1) bacterial assays (Salmonella and E. coli) for reverse gene mutations.

2) an in vitro chromosome aberration assay in a Chinese hamster ovary cell line.

3) an in vivo chromosome aberration assay (micronucleus test) in mice; and

4) a primary DNA damage assay (unscheduled DNA synthesis) in rat hepatocyte primary cultures.

Impairment of Fertility

Pilocarpine oral administration to male and female rats at a dosage of 18 mg/kg/day (100 times the MHOD) resulted in impaired reproductive function, including reduced fertility, decreased sperm motility and morphologic evidence of abnormal sperm. It is unclear whether the reduction in fertility was due to effects on males, females or both. In dogs, exposure to pilocarpine at a dosage of 3 mg/kg/day for 6 months resulted in evidence of impaired spermatogenesis (approximately 55 times the MHOD).