Pilocarpina Biosano

- Alleviation of symptoms of salivary gland hypofunction in patients with severe xerostomia following irradiation for head and neck cancer.

- Treatment of symptoms of dry mouth and dry eyes in patients with Sjögren's syndrome.

- Pilocarpina Biosano is a direct acting miotic indicated for:

- chronic simple glaucoma

- acute (closed angle) glaucoma alone, or in conjunction with other agents to decrease intra-ocular pressure prior to surgical treatment

- miosis - to counteract the effects of cycloplegic or mydriatic eye drops

Isopto® Carpine is indicated for the:

Reduction Of Elevated Intraocular Pressuare (IOP) In Patients With Open-Angle Glaucoma Or Ocular Hypertension

Management Of Acute Angle-Closure Glaucoma

Prevention Of Postoperative Elevated IOP Associated With Laser Surgery

Induction Of Miosis

- For head and neck cancer patients:

The recommended initial dose for adults is 1 tablet of 5 mg three times daily. Tablets should be taken with a glass of water during or directly after meals. The last tablet should always be taken in conjunction with the evening meal. The maximal therapeutic effect is normally obtained after 4 to 8 weeks of therapy. For patients who have not responded sufficiently after 4 weeks and who tolerate the dose of 5 mg three times daily, doses of up to a maximum of 30 mg daily may be considered. However, higher daily doses are probably accompanied by an increase in drug-related adverse effects. Therapy should be discontinued if no improvement in xerostomia is noted after 2 to 3 months of therapy.

- For Sjögren's syndrome patients:

The recommended dose for adults is one tablet of 5 mg four times daily. Tablets should be taken with a glass of water at mealtimes and bedtime. For patients who have not responded sufficiently to a dosage of 5 mg four times daily and who tolerate this dosage, increasing the dose up to a maximum of 30 mg daily, divided over the day, may be considered. Therapy should be discontinued if no improvement in the symptoms of dry mouth and dry eyes is noted after 2 to 3 months.

Special Populations

Use in the elderly:

There is no evidence to suggest that dosage should be different in the elderly.

Paediatric population:

The safety and efficacy of this medicinal product in the paediatric population have not been established.

Use in patients with impaired hepatic function:

Patients with moderate and severe cirrhosis should start treatment on a reduced daily dosage schedule. Depending on the safety and tolerability, the dosage may gradually be increased to the normal daily dosage schedule of 5 mg three times a day.

Use in patients with impaired renal function:

Insufficient information is available to determine the importance of renal excretion of pilocarpine and its metabolites so as to recommend dosage adjustments for patients with renal insufficiency.

Posology

Adults and the elderly

a) In the treatment of open angle glaucoma, the dosage is one or two drops every six hours or as prescribed by the physician.

The strength of the preparation and the frequency of use are determined by the severity of the condition and the response to treatment.

b) When used prior to surgery for acute attacks of closed-angle glaucoma, the dosage is one drop every five minutes until miosis is obtained or as directed by the physician.

c) To overcome weaker mydriatics, the normal dosage is one drop every five minutes until the effect is counteracted or as directed by the physician.

Paediatric population

Based on the infrequency of reports of adverse events in children, and the extensive experience of use of Pilocarpina Biosano in childhood glaucoma, concentrations of up to 2% may be safely used in children.

Treatment should be started with the lowest available dose and concentration in patients under 18 years of age. Depending on clinical response and tolerability, the dose may be increased up to the maximum recommended adult dosage of the 2% Pilocarpina Biosano eye drop solution. Directly after administration of any dose, the lacrimal punctum should be occluded for one minute with a finger to limit systemic exposure.

Method of administration

Eye drops for topical administration into the conjunctival sac.

Reduction Of Elevated Intraocular Pressure (IOP) In Patients With Open-Angle Glaucoma Or Ocular Hypertension

One drop of Isopto® Carpine 1%, 2% or 4% should be applied topically in the eye(s) up to four times daily. Pilocarpine-naïve patients should be started on the 1% concentration as higher concentrations are often not tolerated initially. The frequency of instillation and concentration of Isopto® Carpine are determined by the severity of the elevated intraocular pressure and miotic response of the patient.

To limit systemic exposure to pilocarpine, patients may be instructed to perform punctal occlusion for 2 minutes after instillation of Isopto® Carpine ophthalmic solution.

Management Of Acute Angle-Closure Glaucoma

Prior to Isopto® Carpine use, treatment with secretory suppressants and hyperosmotic agents may be needed to lower IOP below 50 mmHg and relieve iris ischemia. For initial management of acute angleclosure glaucoma, one drop of Isopto® Carpine 1% or 2% may be applied topically in the eye(s) up to three times over a 30-minute period.

If laser iridoplasty or iridomy is used to break the attack, one drop of Isopto® Carpine 4% should be administered prior to the procedure. Following laser iridoplasty, one drop of Isopto® Carpine 1% should be administered four times daily until an iridotomy can be performed.

Prevention Of Postoperative Elevated IOP Associated With Laser Surgery

One drop of Isopto® Carpine 1%, 2% or 4% (or two drops administered five minutes apart) should be applied topically in the eye(s) 15 to 60 minutes prior to surgery.

Induction Of Miosis

One drop of Isopto® Carpine 1%, 2% or 4% (or two drops administered five minutes apart) should be applied topically in the eye(s).

Use With Other Topical Ophthalmic Medications

Isopto® Carpine may be used in combination with beta-blockers, carbonic anhydrase inhibitors, sympathomimetics or hyperosmotic agents. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.

Use In Pediatric Patients

In children under 2 years of age, one drop of Isopto® Carpine 1% should be applied topically in the eye(s) three times daily. Children 2 years of age and over should be dosed as for adults. For the induction of miosis prior to goniotomy or trabeculotomy in children, one drop of Isopto® Carpine 1% or 2% should be applied topically in the eye 15 to 60 minutes prior to surgery.

Hypersensitivity to the active substance or to any of the excipients.

Pilocarpina Biosano is contraindicated in patients with clinically significant, uncontrolled cardiorenal disease, uncontrolled asthma and other chronic disease at risk for cholinergic agonists.

Pilocarpina Biosano is contraindicated in cases where miosis is undesirable, such as in acute iritis.

None.

Caution should be exercised in patients who are known or expected to sweat excessively and who cannot drink enough liquids, since dehydration could develop.

Pilocarpine has been reported to increase airway resistance in asthmatic patients. Also, patients with significant cardiovascular disease may be unable to compensate for transient changes in haemodynamics or heart rhythm induced by pilocarpine. Therefore, Pilocarpina Biosano should be administered to patients with controlled asthma or significant cardiovascular disease only if the benefits are believed to outweigh the risks, and under close medical supervision.

Pilocarpina Biosano should be used with caution in patients with the following illnesses/pathologies:

- Chronic bronchitis and/or chronic obstructive pulmonary disease. These patients have hyperactive airways and may experience adverse effects due to increased bronchial smooth muscle tone and increased bronchial secretions.

- Known or suspected cholelithiasis or biliary tract disease. Contractions of the gallbladder or biliary smooth muscle could precipitate complications including cholecystitis, cholangitis and biliary obstruction.

- Peptic ulceration, due to the risk of increased acid secretion.

- Underlying cognitive or psychiatric disturbances. Cholinergic agonists, like pilocarpine hydrochloride, may have dose-related central nervous system effects.

- Caution should be exercised when administering Pilocarpina Biosano in patients with renal insufficiency.

- Pilocarpine may increase ureteral smooth muscle tone and could theoretically precipitate renal colic (or “ureteral reflux”), particularly in patients with nephrolithiasis.

- Pilocarpina Biosano should be administered with caution in patients with narrow-angle glaucoma.

Although rare, the possibility of systemic absorption should be considered especially in the treatment of acute closed-angle glaucoma where higher doses are administered. It should be used with caution in patients with bronchial asthma, peptic ulceration, urinary tract obstruction, Parkinson's disease, acute heart failure and hypertension.

Fundus examination is advised in all patients before starting Pilocarpina Biosano therapy since retinal detachment has been associated with the use of miotics in susceptible individuals and those with pre-existing retinal disease.

Regular monitoring of visual fields and intra-ocular pressure should be carried out in patients on long term therapy with Pilocarpina Biosano for chronic simple glaucoma.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Poor Illumination

Patients should be advised to exercise caution in night driving and other hazardous occupations in poor illumination. In addition, miotics may cause accommodative spasm. Patients should be advised not to drive or use machinery if vision is not clear.

Pre-Existing Retinal Disease

As with all miotics, rare cases of retinal detachment have been reported when used in certain susceptible individuals and those with pre-existing retinal disease; therefore, a thorough examination of the retina including funduscopy is advised in all patients prior to the initiation of therapy.

Iritis

Isopto® Carpine is not recommended to be used when iritis is present.

Primary Congenital Glaucoma

Caution is advised when using Isopto® Carpine in pediatric patients with primary congenital glaucoma for control of intraocular pressure (IOP) as cases of a paradoxical increase in IOP have been reported. In addition, the use of Isopto® Carpine is not recommended in pediatric patients diagnosed with glaucoma secondary to anterior segment dysgenesis or uveitis (especially if uveitis is active).

Contact Lens Wear

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

There have been no long-term studies done using pilocarpine hydrochloride in animals to evaluate carcinogenic potential.

Use In Specific Populations

Pregnancy

Pregnancy. Category C

Animal reproduction studies have not been conducted with pilocarpine hydrochloride. It is also not known whether pilocarpine hydrochloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Isopto® Carpine should be given to a pregnant woman 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 Isopto® Carpine is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of pilocarpine hydrochloride ophthalmic solution in pediatric patients have been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Patients who experience dizziness during Pilocarpina Biosano treatment should be advised not to drive or operate machinery.

Pilocarpine has been reported to cause impairment of depth perception and visual blurring. The latter may result in decreased visual acuity, especially at night and in patients with central lens changes. If this occurs, patients should be advised not to drive at night or perform hazardous activities in reduced lighting.

The miotic effects of Pilocarpina Biosano cause difficulty in adapting to the dark. Caution is therefore necessary if driving or operating machinery in poorly lit conditions. Pilocarpina Biosano impairs accommodation by paralysis or spasm and patients should not drive or operate machinery if they experience blurred vision.

Most of the adverse experiences observed during Pilocarpina Biosano treatment were a consequence of exaggerated parasympathetic stimulation. These adverse experiences were dose-dependent and usually mild and self-limited. However, severe adverse experiences might occasionally occur and therefore careful monitoring of the patient is recommended.

In controlled clinical trials the following adverse reactions were observed:

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, < 1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Nervous system disorders

Very common: headache

Common: dizziness

Eye disorders

Common: lacrimation; blurred vision; abnormal vision; conjunctivitis; eye pain

Cardiac disorders

Common: flushing (vasodilatation); hypertension; palpitations

Respiratory, thoracic and mediastinal disorders

Common: rhinitis

Gastrointestinal disorders

Common: dyspepsia; diarrhoea; abdominal pain; nausea, vomiting; constipation, increased salivation

Uncommon: flatulence

Skin and subcutaneous tissue disorders

Very common: sweating

Common: allergic reactions, including rash, pruritus

Renal and urinary disorders

Very common: increased urinary frequency

Uncommon: urinary urgency

General disorders and administration site conditions

Very common: flu syndrome

Common: asthenia, chills

There is no indication of a difference between older and younger patients receiving Pilocarpina Biosano as regards reporting adverse experiences, except for dizziness, which was reported significantly more often by patients aged over 65 years.

The following adverse effects, which are due to the intrinsic pharmacological properties of pilocarpine, have been published in the medical literature: respiratory distress, gastro-intestinal spasm, atrioventricular block, tachycardia, bradycardia, cardiac arrhythmia, hypotension, shock, tremors, and mental status changes including memory loss, hallucinations, lability of affect, confusion, agitation.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Adverse drug reactions from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: http://www.mhra.gov.uk/yellowcard.

Clinical Studies 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.

The safety data described below reflect exposure in four controlled clinical trials of 90 days to 2 years duration in 317 patients diagnosed with open-angle glaucoma or ocular hypertension. In the four clinical trials, patients were treated with Isopto® Carpine 2%, two to four times daily or with pilocarpine 1%, 1.75% or 2% in fixed combination with betaxolol 0.25%, two or three times daily.The most frequently reported adverse reactions occurring in ≥ 5% of patients in the pilocarpine 2% populations were: headache/browache, accommodative change, blurred vision, eye irritation, visual impairment (dim, dark, or “jumping” vision), and eye pain.

The adverse reaction profile reported for the use of Isopto® Carpine in pediatric patients is comparable to that seen in adult patients.

Overdose may lead to a 'cholinergic crisis' characterised by both muscarinic and nicotinic effects.

Signs of overdose due to muscarinic effects may include abdominal cramps, diarrhoea, nausea and vomiting, involuntary defecation and urination, sweating, salivation, increased bronchial secretions, miosis, bradycardia and hypotension.

Nicotinic effects may include involuntary twitching, fasciculations and generalised weakness.

Parenteral atropine may be used as an antidote to the muscarinic effects. Supportive treatment should be given as required; artificial respiration should be instituted if respiratory depression is severe.

If Pilocarpina Biosano is accidentally ingested, emesis should be induced or gastric lavage performed. The patient should be monitored for signs of Pilocarpina Biosano toxicity such as increased salivation and sweating, lacrimation, nausea, vomiting and diarrhoea. If these occur, therapy with an anticholinergic such as atropine may be required.

Systemic toxicity following topical ocular administration of pilocarpine is rare, but occasionally patients who are sensitive may develop sweating and gastrointestinal overactivity following the suggested dosage and administration. Overdosage can produce sweating, salivation, nausea, tremors and slowing of the pulse and a decrease in blood pressure. In moderate overdosage, spontaneous recovery is to be expected and is aided by intravenous fluids to compensate for dehydration. For patients demonstrating severe poisoning, atropine, the pharmacologic antagonist to pilocarpine, should be used.

Pharmacotherapeutic group: Parasympathominetic, ATC code: N07A X01.

Pilocarpine is a cholinergic parasympathomimetic agent exerting a broad spectrum of pharmacologic effects with predominant muscarinic action. Pilocarpine, in appropriate dosage, can increase secretion by exocrine glands such as the sweat, salivary, lacrimal, gastric, pancreatic and intestinal glands and the mucous cells of the respiratory tract.

Dose-related smooth muscle stimulation of the intestinal tract may cause increased tone, increased motility, spasm and tenesmus. Bronchial smooth muscle tone may increase. The tone and motility of urinary tract, gallbladder and biliary duct smooth muscle may be enhanced.

Pilocarpine may have paradoxical effects on the cardiovascular system. The expected effect of a muscarinic agonist is vasodepression, but administration of pilocarpine may produce hypertension after a brief episode of hypotension. Bradycardia and tachycardia have both been reported with use of pilocarpine.

In a study in healthy male volunteers an increase in salivary flow following single 5 and 10 mg doses of Pilocarpina Biosano was noted 20 minutes after administration, and lasted for 3 to 5 hours with a peak at 1 hour.

- For head and neck cancer patients:

In two 12-week randomised, double-blind placebo-controlled clinical studies in patients with xerostomia resulting from irradiation to the head and neck for cancer, Pilocarpina Biosano treatment reduced dryness of the mouth; in one of these studies this did not occur until after 12 weeks of treatment. Also, Pilocarpina Biosano treatment increased salivary flow. The greatest improvement in dryness was noted in patients with no measurable salivary flow at baseline.

In both studies, some patients noted improvement in the overall condition of xerostomia, speaking without drinking liquids, and mouth comfort, and there was reduced use of concomitant therapy (i.e. artificial saliva) for dry mouth.

- For Sjögren's syndrome patients:

Two separate 12-week randomised, double-blind placebo-controlled clinical studies were conducted in patients diagnosed with primary or secondary Sjögren's syndrome. In both studies, the majority of patients best fit the European criteria for having primary Sjögren's syndrome. The ability of Pilocarpina Biosano to stimulate saliva production was assessed. Relative to placebo, an increase in the amount of saliva being produced was observed following the first dose and was maintained throughout the duration of the trials in an approximate dose response fashion.

Compared to placebo a statistically significant global improvement for both dry mouth and dry eyes was observed.

Efficacy of Pilocarpina Biosano has not been established in patients with the Sjögren's syndrome during long term treatment (>12 weeks).

Pharmacotherapeutic group: parasympathomimetics

ATC code: S01EB01

Pilocarpina Biosano is an alkaloid of natural plant origin, which is a direct-acting cholinergic agonist. It acts primarily at muscarinic receptor sites both peripherally and centrally, affecting smooth muscle, the cardiovascular system and exocrine glands.

The precise mechanism by which Pilocarpina Biosano reduces intra-ocular pressure has not been established, though it is believed to involve direct stimulation of the longitudinal muscle of the ciliary body, which in turn affects the scleral spur, widening the trabecular spaces and allowing for increased aqueous flow. Pilocarpina Biosano may also decrease aqueous formation with long term administration. Due to its activity at the muscarinic receptor sites of the ciliary muscles and iris sphincter, Pilocarpina Biosano causes varying degrees of accommodation spasm and pupillary constriction.

Paediatric population

There are literature reports of the ocular use of Pilocarpina Biosano in concentrations up to 2% in patients aged 1 month and older. However, information on the dose and strength used is limited. Safety data do not suggest any significant safety issues in children, or any difference between the safety profiles of Pilocarpina Biosano in children and adults.

Absorption

In a multiple-dose pharmacokinetic study in volunteers given 5 or 10 mg of pilocarpine hydrochloride three times daily for two days, the T_max after the final dose was approximately 1 hour, the elimination T½ was approximately 1 hour, and the mean C_max were 15 ng/ml and 41 ng/ml for the 5 and 10 mg doses, respectively.

When taken with a high-fat meal, there was a decrease in the rate of absorption of pilocarpine from Pilocarpina Biosano tablets. Mean T_max were 1.47 and 0.87 hours and mean C_max were 51.8 and 59.2 ng/ml for fed and fasted male volunteers, respectively.

Distribution

Pilocarpine is extensively distributed with an apparent volume of distribution of 2.1 L/kg. Data from animal studies indicates that pilocarpine is distributed into breast milk at concentrations similar to plasma. Preclinical data also suggests that pilocarpine can cross the blood brain barrier at high dose. Pilocarpine does not bind to plasma proteins.

Metabolism

Pilocarpine is primarily metabolized by CYP2A6 and has demonstrated a capacity to inhibit CYP2A6 in vitro. Serum esterases are also involved in the biotransformation of pilocarpine to pilocarpic acid.

Elimination

Approximately 35% of dose is eliminated as 3-hydroxypilocarpine in urine and 20% of dose is excreted unchanged in the urine. Mean elimination half-lives for pilocarpine is 0.76 and 1.35 hours after repeated oral doses of 5 and 10 mg of pilocarpine hydrochloride, respectively.

Elderly

Pilocarpine AUC values in elderly male volunteers were comparable to those in younger males. In a small number of healthy elderly female volunteers the mean AUC was approximately twice that of elderly and young male volunteers due to reduced volumes of distribution. However, the observed difference in pharmacokinetics was not reflected in the incidence of adverse events between young and elderly female patients. No dosage adjustment is required in elderly subjects.

Renal impairment

A pharmacokinetic study of pilocarpine in patients with mild and moderately impaired renal function showed that there was no significant difference in clearance and exposure compared with subjects with normal renal function.

Onset of miosis after topical administration of a 1% solution of Pilocarpina Biosano hydrochloride or nitrate to the conjunctival sac occurs within 10-30 minutes, with maximal effect within 30 minutes. Miosis usually persists for 4-8 hours, rarely, up to 20 hours. Reduction of intra-ocular pressure is evident within 60 minutes, peaks within 75 minutes and, depending on the concentration of Pilocarpina Biosano used, persists for 4-14 hours. Spasms of accommodation commence in about 15 minutes and persist for 2-3 hours.

Systemic exposure to pilocarpine was evaluated in 14 healthy subjects administered 2 drops of Isopto® Carpine (pilocarpine hydrochloride ophthalmic solution) 4% to both eyes four times daily for eight days. A comparison of Cmax values on Days 5 and 8 indicated that pilocarpine concentrations in plasma reached steady-state following topical administration of Isopto® Carpine 4%. The mean (SD) Cmax and AUC0-last values on Day 8 were 3.7 (3.2) ng/mL and 7.7 (8.4) ng×hour/mL, respectively. The Tmax values on Day 8 ranged from 0.5 to 1 hour.

Genotoxicity and carcinogenicity:

Pilocarpine did not indicate a genotoxic potential in a series of in vitro and in vivo genotoxicity studies. In lifetime oral carcinogenicity studies in rodents Pilocarpine did not cause an increase in tumour incidence in mice, but was associated with an increased incidence in benign pheochromocytomas in rats at >15 times the exposure at the maximum recommended human dose and therefore not considered relevant to clinical use. Preclinical data revealed no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.

Fertility

Animal studies have shown adverse effects on the male reproductive tract following chronic exposures to pilocarpine. Impaired spermatogenesis was observed in rats and dogs following 28-day and 6-month oral exposures respectively. Histopathological changes were also observed in the testes and bulbourethral glands of mice given pilocarpine for 2 years.

The safety margin for the effects in humans is unknown. However, body surface area [mg/m²] comparisons suggest that the lowest dose associated with impaired fertility, (3 mg/kg/day in the dog), is approximately 3 times the maximum recommended human dose, therefore a risk to humans cannot be ruled out. A study in rats has also indicated a possible impairment of female fertility.

Reproductive toxicity:

Studies in pregnant rats showed treatment-related reductions in the mean fetal body weight and increases in the incidence of skeletal variations [at approximately 26 times the maximum recommended dose for a 50 kg human (based on comparisons of body surface area [mg/m²]. These effects occurred at doses that were maternally toxic. There was no evidence of a teratogenic effect in the animal studies. Treatment related increases in the incidence of stillbirths with decreased neonatal survival and reduced mean body weight of pups were observed in pre- and postnatal studies. A safety margin for these effects cannot be calculated. However, body surface area [mg/m2] comparisons suggest that the effect occurred at approximately 5 times the maximum recommended dose for a 50 kg human. The clinical relevance of these findings is unknown.

None available.

Not applicable

Soft contact lenses absorb water soluble compounds such as Pilocarpina Biosano and its salts and the preservative benzalkonium chloride, and should therefore not be worn when administering Pilocarpina Biosano eye drops.

No special requirements.

No special requirements for disposal.

Any unused medicinal product or waste material should disposed of in accordance with local requirements.