Pilocarpine

S01E - Antiglaucoma preparations and miotics ATC S01EB51 Small molecule approved 1974 Oral Topical Natural product

JFDA label: Fotil Eye Drops

Mechanism of Action

Agonist of Muscarinic acetylcholine receptor M3 — Muscarinic acetylcholine receptor M3 agonist; Agonist of Muscarinic acetylcholine receptor M1 — Muscarinic acetylcholine receptor M1 agonist

Target	Action	Gene / class
Muscarinic acetylcholine receptor M1 efficacy	AGONIST	CHRM1
Muscarinic acetylcholine receptor M3 efficacy	AGONIST	CHRM3

Indications

Approved

Glaucoma — glaucoma
Glaucoma, Angle-Closure — angle-closure glaucoma
Glaucoma, Open-Angle — open-angle glaucoma
Miosis — Miosis
Ocular Hypertension — ocular hypertension
Sjogren's Syndrome — Sjogren syndrome
Xerostomia — xerostomia

Off-label

Dry Eye Syndromes
Presbyopia

Contraindications

Source: openFDA

Pilocarpine hydrochloride tablets are contraindicated in patients with uncontrolled asthma, known hypersensitivity to pilocarpine, and when miosis is undesirable, e.g., in acute iritis and in narrow-angle (angle closure) glaucoma. Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (5)

Rare Arrhythmia · Mucous Membrane Abnormality Cardiovascular Bradycardia · Myocardial Infarction Digestive Anorexia · Palpitations · Photosensitivity Reaction Cardiovascular Angina Pectoris

Vascular disorders (2)

Rare Hypertension · Hypotension

Nervous system disorders (3)

Rare Intracranial Hemorrhage · Malignant Glaucoma · Migraine

Blood and lymphatic system disorders (1)

Rare Tongue Disorder Hematologic Leukopenia

Gastrointestinal disorders (4)

Rare Esophagitis · Gastrointestinal Disorder · Increased Appetite · Syncope Digestive Anorexia

Skin and subcutaneous tissue disorders (2)

Rare Dermatitis · Eyelid Twitching

Psychiatric disorders (5)

Rare Agitation · And Visual Hallucination · Confusion · Delusion · Depression

Investigations (1)

Rare Ecg Abnormality

General disorders and administration site conditions (16)

Very Common Years

Rare A-V Block · Causal Relation Is Unknown Body As A Whole Body Odor · Causal Relation Is Unknown Body As A Whole Chest Pain · Ciliary Congestion · Cyst · Death · Hypothermia · Iris Cysts · Lymphadenopat · Macular Hole · Middle Ear Disturbance · Moniliasis · Neck Pain · Neck Rigidity · Shock

Dosing

Source: openFDA

Regardless of the indication, the starting dose in patients with moderate hepatic impairment should be 5 mg twice daily, followed by adjustment based on therapeutic response and tolerability. Patients with mild hepatic insufficiency do not require dosage reductions. The use of pilocarpine in patients with severe hepatic insufficiency is not recommended. If needed, refer to the Hepatic Insufficiency subsection of the Precautions section of this label for definitions of mild, moderate and severe hepatic impairment. Head & Neck Cancer Patients The recommended initial dose of pilocarpine hydrochloride tablets is 5 mg taken three times a day. Dosage should be titrated according to therapeutic response and tolerability. The usual dosage range is up to 15 mg per day to 30 mg per day (Not to exceed 10 mg per dose). Although early improvement may be realized, at least 12 weeks of uninterrupted therapy with pilocarpine hydrochloride tablets may be necessary to assess whether a beneficial response will be achieved. The incidence of the most common adverse events increases with dose. The lowest dose that is tolerated and effective should be used for maintenance. Sjogren’s syndrome Patients The recommended dose of pilocarpine hydrochloride tablets is one tablet (5 mg) taken four times a day. Efficacy was established by 6 weeks of use.

Warnings & Precautions

Source: openFDA

Warnings & Precautions

Cardiovascular Disease Patients with significant cardiovascular disease may be unable to compensate for transient changes in hemodynamics or rhythm induced by pilocarpine. Pulmonary edema has been reported as a complication of pilocarpine toxicity from high ocular doses given for acute angle-closure glaucoma. Pilocarpine should be administered with caution in and under close medical supervision of patients with significant cardiovascular disease. Ocular Ocular formulations of pilocarpine have been reported to cause visual blurring which may result in decreased visual acuity, especially at night and in patients with central lens changes, and to cause impairment of depth perception. Caution should be advised while driving at night or performing hazardous activities in reduced lighting. Pulmonary Disease Pilocarpine has been reported to increase airway resistance, bronchial smooth muscle tone, and bronchial secretions. Pilocarpine hydrochloride should be administered with caution to and under close medical supervision in patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease requiring pharmacotherapy.

Pregnancy & Lactation

Pregnancy

Lactation

Caution Hale L3

Because no information is available on the use of oral pilocarpine during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

LactMed: monitor the infant.

Chemistry & Properties

Formula	C11H16N2O2
Molecular weight	208.26 g/mol
IUPAC name	(3S,4R)-3-ethyl-4-[(3-methylimidazol-4-yl)methyl]oxolan-2-one
CAS	92-13-7
PubChem CID	5910
InChIKey	`QCHFTSOMWOSFHM-WPRPVWTQSA-N`
logP	1.16 (XLogP 1.1)
Polar surface area	44.12 Å²
H-bond acceptors / donors	4 / 0
Drug-likeness (QED)	0.70
Lipinski violations	0

SMILES

CC[C@@H]1C(=O)OC[C@@H]1Cc1cncn1C

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	1.128 h
Volume of distribution	1.052 L/kg
Protein binding	15.5%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—
CYP2C8	Inhibitor	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 4)

Target	Action	Affinity
M4 receptor (CHRM4)	Agonist	pKi 5.2
M1 receptor (CHRM1)	Agonist	pKi 5.1
M3 receptor (CHRM3)	Agonist	pKi 5.1
M5 receptor (CHRM5)	Agonist	pKi 5.0

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (27, DDInter)

Interacting drug	Severity	Management
Siponimod	major
Aclidinium	moderate
Alectinib	moderate
Atropine	moderate
Atropine (ophthalmic)	moderate
Brigatinib	moderate
Clidinium	moderate
Crizotinib	moderate
Cyclizine	moderate
Dicyclomine	moderate
Fingolimod	moderate
Glycopyrronium	moderate
Glycopyrronium (topical)	moderate
Hyoscyamine	moderate
Ipratropium	moderate
Meclizine	moderate
Mepenzolate	moderate
Methscopolamine	moderate
Ozanimod	moderate
Propantheline	moderate
Revefenacin	moderate
Scopolamine	moderate
Scopolamine (ophthalmic)	moderate
Thalidomide	moderate
Tiotropium	moderate
Trospium	moderate
Umeclidinium	moderate

Registered Products (4)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Apicarpin 2% eye drops	Ophthalmic Solution 2 %	10 ml	Amman Pharmaceutical Indusries	1.250
Apicarpin 4% eye drops	Ophthalmic Solution 4 %	10 ml	Amman Pharmaceutical Indusries	1.350
Fotil Eye Drops	Ophthalmic Solution 2 %, 0.5 %	5 ml	THE ARAB DRUG STORE P.S.C	3.660
Fotil Forte Eye Drops	Ophthalmic Solution 4 %, 0.5 %	5 ml	THE ARAB DRUG STORE P.S.C	3.790