WARNINGS SECTION.


WARNINGS Cardiovascular Disease: Patients with significantcardiovascular disease may be unable to compensatefor transient changes in hemodynamics or rhythminduced by pilocarpine. Pulmonary edema has beenreported as a complication of pilocarpine toxicity fromhigh ocular doses given for acute angle-closure glaucoma.Pilocarpine should be administered with caution in andunder close medical supervision of patients with significantcardiovascular disease. Ocular: Ocular formulations of pilocarpine have beenreported to cause visual blurring which may result indecreased visual acuity, especially at night and in patientswith central lens changes, and to cause impairment ofdepth perception. Caution should be advised whiledriving at night or performing hazardous activities inreduced lighting. Pulmonary Disease: Pilocarpine has been reported toincrease airway resistance, bronchial smooth muscletone, and bronchial secretions. Pilocarpine hydrochlorideshould be administered with caution to and under closemedical supervision in patients with controlled asthma,chronic bronchitis, or chronic obstructive pulmonarydisease requiring pharmacotherapy.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL NDC 62856-775-10 Tablets SALAGEN (pilocarpine hydrochloride) 7.5 mg 100 film coated tablets- 7.5 mg each Rx Only

ADVERSE REACTIONS SECTION.


ADVERSE REACTIONS Head & Neck Cancer Patients: In controlled studies, 217 patients received pilocarpine,of whom 68% were men and 32% were women. Racedistribution was 91% Caucasian, 8% Black, and 1% ofother origin. Mean age was approximately 58 years.The majority of patients were between 50 and 64 years(51%), 33% were 65 years and older and 16% wereyounger than 50 years of age.The most frequent adverse experiences associatedwith SALAGEN Tablets were a consequence of theexpected pharmacologic effects of pilocarpine. Adverse Event Pilocarpine HCI Placebo 10 mg t.i.d. (30 mg/day) 5 mg t.i.d. (15 mg/day) (t.i.d.) Sweating N=121/68% N=141/29% N=152/9% Nausea 15 6 4 Rhinitis 14 5 7 Diarrhea 7 4 5 Chills 15 3 <1 Flushing 13 8 3 Urinary Frequency 12 9 7 Dizziness 12 5 4 Asthenia 12 6 3 In addition, the following adverse events (3% incidence)were reported at dosages of 15-30 mg/day in thecontrolled clinical trials: Adverse Event Pilocarpine HCI Placebo 5-10 mg t.i.d. (15-30 mg/day) (t.i.d.) Headache N=212/11% N=152/8% Dyspepsia 7 5 Lacrimation 6 8 Edema 5 4 Abdominal Pain 4 4 Amblyopia 4 2 Vomiting 4 1 Pharyngitis 3 8 Hypertension 3 1 The following events were reported with treated headand neck cancer patients at incidences of 1% to 2%at dosages of 7.5 to 30 mg/day: abnormal vision,conjunctivitis, dysphagia, epistaxis, myalgias, pruritus,rash, sinusitis, tachycardia, taste perversion, tremor,voice alteration. The following events were reported rarely in treatedhead and neck cancer patients (<1%):Causal relation is unknown. Body as a whole: body odor, hypothermia, mucousmembrane abnormality Cardiovascular: bradycardia, ECG abnormality, palpitations,syncope Digestive: anorexia, increased appetite, esophagitis,gastrointestinal disorder, tongue disorder Hematologic: leukopenia, lymphadenopathy Nervous: anxiety, confusion, depression, abnormaldreams, hyperkinesia, hypesthesia, nervousness,parethesias, speech disorder, twitching Respiratory: increased sputum, stridor, yawning Skin: seborrhea Special senses: deafness, eye pain, glaucoma Urogenital: dysuria, metrorrhagia, urinary impairment In long-term treatment were two patients with underlyingcardiovascular disease of whom one experienced amyocardial infarct and another an episode of syncope.The association with drug is uncertain. Sjogrens Syndrome Patients: In controlled studies, 376patients received pilocarpine, of whom 5% were menand 95% were women. Race distribution was 84%Caucasian, 9% Oriental, 3% Black, and 4% of otherorigin. Mean age was 55 years. The majority ofpatients were between 40 and 69 years (70%), 16%were 70 years and older and 14% were younger than40 years of age. Of these patients, 161/629 (89/376receiving pilocarpine) were over the age of 65 years.The adverse events reported by those over 65 yearsand those 65 years and younger were comparableexcept for notable trends for urinary frequency, diarrhea,and dizziness. The incidences of urinary frequency anddiarrhea in the elderly were about double those of thenon-elderly. The incidence of dizziness was about threetimes as high in the elderly as in the non-elderly. Theseadverse experiences were not considered to be serious.In the 2 placebo-controlled studies, the most commonadverse events related to drug use were sweating, urinaryfrequency, chills, and vasodilatation (flushing). The mostcommonly reported reason for patient discontinuationof treatment was sweating. Expected pharmacologiceffects of pilocarpine include the following adverseexperiences associated with SALAGEN Tablets: Adverse Event Pilocarpine HCI Placebo 5 mg q.i.d. (20 mg/day) (q.i.d) Sweating N=255/40% N=253/7% Urinary Frequency 10 4 Nausea 9 9 Flushing 9 2 Rhinitis 7 8 Diarrhea 6 7 Chills 4 2 Increased Salivation 3 0 Asthenia 2 2 In addition, the following adverse events(3% incidence)were reported at dosages of 20 mg/day in the controlledclinical trials: Adverse Event Pilocarpine HCI Placebo 5 mg q.i.d. ( 20 mg/day) (q.i.d ) Headache N=255/13% N=253/19% Flu Syndrome 9 9 Dyspepsia 7 7 Dizziness 6 7 Pain 4 2 Sinusitis 4 5 Abdominal Pain 3 4 Vomiting 3 1 Pharyngitis 2 5 Rash 2 3 Infection 2 6 The following events were reported in Sjogrens patientsat incidences of 1% to 2% at dosing of 20 mg/day:accidental injury, allergic reaction, back pain, blurredvision, constipation, increased cough, edema, epistaxis,face edema, fever, flatulence, glossitis, lab test abnormalities,including chemistry, hematology, and urinalysis,myalgia, palpitation, pruritus, somnolence, stomatitis,tachycardia, tinnitus, urinary incontinence, urinary tractinfection, and vaginitis. The following events were reported rarely in treatedSjogrens patients (<1%) at dosing of 10-30 mg/day:Causal relation is unknown. Body as a whole: chest pain, cyst, death, moniliasis,neck pain, neck rigidity, photosensitivity reaction Cardiovascular: angina pectoris, arrhythmia, ECGabnormality, hypotension, hypertension, intracranialhemorrhage, migraine, myocardial infarction Digestive: anorexia, bilirubinemia, cholelithiasis, colitis,dry mouth, eructation, gastritis, gastroenteritis, gastrointestinaldisorder, gingivitis, hepatitis, abnormalliver function tests, melena, nausea & vomiting,pancreatitis, parotid gland enlargement, salivarygland enlargement, sputum increased, taste loss,tongue disorder, tooth disorder Hematologic: hematuria, lymphadenopathy, abnormalplatelets, thrombocythemia, thrombocytopenia,thrombosis, abnormal WBC Metabolic and Nutritional: peripheral edema, hypoglycemia Musculoskeletal: arthralgia, arthritis, bone disorder,spontaneous bone fracture, pathological fracture,myasthenia, tendon disorder, tenosynovitis Nervous: aphasia, confusion, depression, abnormaldreams, emotional lability, hyperkinesia, hypesthesia,insomnia, leg cramps, nervousness, parethesias,abnormal thinking, tremor Respiratory: bronchitis, dyspnea, hiccup, laryngismus,laryngitis, pneumonia, viral infection, voice alteration Skin: alopecia, contact dermatitis, dry skin, eczema,erythema nodosum, exfoliative dermatitis, herpessimplex, skin ulcer, vesiculobullous rash Special Senses: cataract, conjunctivitis, dry eyes, eardisorder, ear pain, eye disorder, eye hemorrhage,glaucoma, lacrimation disorder, retinal disorder, tasteperversion, abnormal vision Urogenital: breast pain, dysuria, mastitis, menorrhagia,metrorrhagia, ovarian disorder, pyuria, salpingitis,urethral pain, urinary urgency, vaginal hemorrhage,vaginal moniliasis The following adverse experiences have been reportedrarely with ocular pilocarpine: A-V block, agitation, ciliarycongestion, confusion, delusion, depression, dermatitis,middle ear disturbance, eyelid twitching, malignantglaucoma, iris cysts, macular hole, shock, and visualhallucination.

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE SALAGEN Tablets areindicated for 1) the treatment of symptoms of drymouth from salivary gland hypofunction caused byradiotherapy for cancer of the head and neck; and2) the treatment of symptoms of dry mouth in patientswith Sjogrens Syndrome.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION Regardless of the indication, the starting dose in patientswith moderate hepatic impairment should be 5 mgtwice daily, followed by adjustment based on therapeuticresponse and tolerability. Patients with mild hepaticinsufficiency do not require dosage reductions. The useof pilocarpine in patients with severe hepatic insufficiencyis not recommended. If needed, refer to the Hepatic Insufficiency subsection of the Precautions section ofthis label for definitions of mild, moderate and severehepatic impairment. Head & Neck Cancer Patients:The recommended initialdose of SALAGEN Tablets is 5 mg taken three times aday. Dosage should be titrated according to therapeuticresponse and tolerance. The usual dosage range is upto 15-30 mg per day. (Not to exceed 10 mg per dose.)Although early improvement may be realized, at least12 weeks of uninterrupted therapy with SALAGENTablets may be necessary to assess whether a beneficialresponse will be achieved. The incidence of the mostcommon adverse events increases with dose. The lowestdose that is tolerated and effective should be usedfor maintenance. Sjogrens Syndrome Patients: The recommended doseof SALAGEN Tablets is 5 mg taken four times a day.Efficacy was established by 6 weeks of use.

SPL UNCLASSIFIED SECTION.


MANAGEMENT OF OVERDOSE Fatal overdosage withpilocarpine has been reported in the scientific literatureat doses presumed to be greater than 100 mg in twohospitalized patients. 100 mg of pilocarpine is consideredpotentially fatal. Overdosage should be treated withatropine titration (0.5 mg to 1.0 mg given subcutaneouslyor intravenously) and supportive measures to maintainrespiration and circulation. Epinephrine (0.3 mg to 1.0 mg,subcutaneously or intramuscularly) may also be of valuein the presence of severe cardiovascular depression orbronchoconstriction. It is not known if pilocarpine isdialyzable.

HOW SUPPLIED SECTION.


HOW SUPPLIED SALAGEN Tablets, 5 mg, are white, film coated,debossed round tablets, coded SAL 5. Each tabletcontains 5 mg pilocarpine hydrochloride. They aresupplied as follows:NDC 62856-705-10 bottles of 100 Store up to 25C (77F); excursions permitted to15-30C (59-86F). SALAGEN Tablets, 7.5 mg, are blue, film coated,debossed round tablets, coded SAL 7.5. Each tabletcontains 7.5 mg pilocarpine hydrochloride. They aresupplied as follows:NDC 62856-775-10 bottles of 100 Store up to 25C (77F); excursions permitted to15-30C (59-86F). Manufactured by: Patheon Inc., Ontario, L5N 7K9 Manufactured for: Eisai Inc. Woodcliff Lake, NJ 07677 2018Eisai Inc. June 2018 SALAGEN is a registered trademark of Eisai Inc.

DESCRIPTION SECTION.


DESCRIPTION SALAGEN Tablets contain pilocarpinehydrochloride, a cholinergic agonist for oral use.Pilocarpine hydrochloride is a hygroscopic, odorless, bitter tasting white crystal or powder which is solublein water and alcohol and virtually insoluble in mostnon-polar solvents. Pilocarpine hydrochloride, with achemical name of (3S-cis)-2(3H)-Furanone, 3-ethyl-dihydro-4-[(1-methyl-1H-imidazol-5-yl)methyl] mono-hydrochloride, has a molecular weight of 244.72. Each 5 mg SALAGEN Tablet for oral administrationcontains 5 mg of pilocarpine hydrochloride. Inactiveingredients in the tablet, the tablets film coating, andpolishing are: carnauba wax, hypromellose, microcrystallinecellulose, stearic acid, titanium dioxide and otheringredients. Each 7.5 mg SALAGEN Tablet for oral administrationcontains 7.5 mg of pilocarpine hydrochloride. Inactiveingredients in the tablet, the tablets film coating, andpolishing are: carnauba wax, hypromellose, microcrystallinecellulose, stearic acid, titanium dioxide, FD&Cblue#2 aluminum lake, and other ingredients.

PRECAUTIONS SECTION.


PRECAUTIONS General Pilocarpine toxicity is characterized by anexaggeration of its parasympathomimetic effects.These may include: headache, visual disturbance, lacrimation, sweating, respiratory distress, gastrointestinalspasm, nausea, vomiting, diarrhea, atrioventricular block, tachycardia, bradycardia, hypotension, hypertension, shock, mental confusion, cardiac arrhythmia, and tremors. The dose-related cardiovascular pharmacologic effects of pilocarpine include hypotension, hypertension, bradycardia, and tachycardia. Pilocarpine should be administered with caution topatients with known or suspected cholelithiasis or biliarytract disease. Contractions of the gallbladder or biliarysmooth muscle could precipitate complications includingcholecystitis, cholangitis, and biliary obstruction. Pilocarpine may increase ureteral smooth muscle toneand could theoretically precipitate renal colic (or ureteralreflux), particularly in patients with nephrolithiasis. Cholinergic agonists may have dose-related centralnervous system effects. This should be consideredwhen treating patients with underlying cognitive orpsychiatric disturbances. Hepatic Insufficiency: Based on decreased plasmaclearance observed in patients with moderate hepaticimpairment, the starting dose in these patients shouldbe 5 mg twice daily, followed by adjustment based ontherapeutic response and tolerability. Patients with mildhepatic insufficiency (Child-Pugh score of 5-6) do notrequire dosage reductions. To date, pharmacokineticstudies in subjects with severe hepatic impairment(Child-Pugh score of 10-15) have not been carried out.The use of pilocarpine in these patients is not recommended. Child - Pugh Scoring System for Hepatic Impairment Clinical and Biochemical Measurements Points Scored for Increasing Abnormality 1 2 3 Encephalopathy (grade )* None 1 and 2 3 and 4 Ascites Absent Slight Moderate Bilirubin (mg. per 100 mL) 1-2 2-3 >3 Albumin (g. per 100 mL) 3-5 2.8-3.5 6 For Primary Biliary Cirrhosis:-Bilirubin(mg. per100mL) 1-4 4-10 >10 * According to grading of Trey C, Burns D, and Saunders S. Treatment of hepatic coma byexchange blood transfusion. N Engl J Med. 1966; 274:473-481. Reference: Pugh RNH, Murray-Lyon IM, Dawson JL,Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Brit J Surg. 1973;60:646-9. Information for Patients Patients should be informedthat pilocarpine may cause visual disturbances, especiallyat night, that could impair their ability to drive safely.If a patient sweats excessively while taking pilocarpinehydrochloride and cannot drink enough liquid, the patientshould consult a physician. Dehydration may develop. Drug Interactions Pilocarpine should be administeredwith caution to patients taking beta-adrenergic antagonistsbecause of the possibility of conduction disturbances.Drugs with parasympathomimetic effects administeredconcurrently with pilocarpine would be expected toresult in additive pharmacologic effects. Pilocarpinemight antagonize the anticholinergic effects of drugsused concomitantly. These effects should be consideredwhen anticholinergic properties may be contributing tothe therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium).While no formal drug interaction studies have beenperformed, the following concomitant drugs were usedin at least 10% of patients in either or both Sjogrensefficacy studies: acetylsalicylic acid, artificial tears,calcium, conjugated estrogens, hydroxychloroquinesulfate, ibuprofen, levothyroxine sodium, medroxyprogesteroneacetate, methotrexate, multivitamins, naproxen,omeprazole, paracetamol, and prednisone. Carcinogenesis, Mutagenesis, Impairment of Fertility Lifetime oral carcinogenicity studies wereconducted in CD-1 mice and Sprague-Dawley rats.Pilocarpine did not induce tumors in mice at anydosage studied (up to 30 mg/kg/day, which yielded asystemic exposure approximately 50 times larger thanthe maximum systemic exposure observed clinically).In rats, a dosage of 18 mg/kg/day, which yielded asystemic exposure approximately 100 times larger thanthe maximum systemic exposure observed clinically, resulted in a statistically significant increase in theincidence of benign pheochromocytomas in both malesand females, and a statistically significant increase inthe incidence of hepatocellular adenomas in femalerats. The tumorigenicity observed in rats was observedonly at a large multiple of the maximum labeled clinicaldose, and may not be relevant to clinical use. No evidence that pilocarpine has the potential to cause genetic toxicity was obtained in a series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosomeaberration assay in a Chinese hamster ovary cell line; 3) an in vivo chromosome aberration assay (micronucleus test) in mice; and 4) a primary DNA damageassay (unscheduled DNA synthesis) in rat hepatocyte primary cultures. Oral administration of pilocarpine to male and femalerats at a dosage of 18 mg/kg/day, which yielded asystemic exposure approximately 100 times larger thanthe maximum systemic exposure observed clinically, resulted in impaired reproductive function, includingreduced fertility, decreased sperm motility, and morphologicevidence of abnormal sperm. It is unclearwhether the reduction in fertility was due to effectson male animals, female animals, or both males andfemales. In dogs, exposure to pilocarpine at a dosageof 3 mg/kg/day (approximately 3 times the maximumrecommended human dose when compared on thebasis of body surface area (mg/m2) estimates) for sixmonths resulted in evidence of impaired spermatogenesis.The data obtained in these studies suggest thatpilocarpine may impair the fertility of male and femalehumans. SALAGEN Tablets should be administered toindividuals who are attempting to conceive a child onlyif the potential benefit justifies potential impairmentof fertility. Pregnancy: Teratogenic Effects Pilocarpine was associatedwith a reduction in the mean fetal body weight and anincrease in the incidence of skeletal variations whengiven to pregnant rats at a dosage of 90 mg/kg/day(approximately 26 times the maximum recommendeddose for a 50 kg human when compared on the basisof body surface area (mg/m2) estimates). These effectsmay have been secondary to maternal toxicity. Inanother study, oral administration of pilocarpine tofemale rats during gestation and lactation at a dosageof 36 mg/kg/day (approximately 10 times the maximumrecommended dose for a 50 kg human when comparedon the basis of body surface area (mg/m2) estimates)resulted in an increased incidence of stillbirths;decreased neonatal survival and reduced mean bodyweight of pups were observed at dosages of 18 mg/kg/day(approximately 5 times the maximum recommendeddose for a 50 kg human when compared on the basisof body surface area (mg/m2) estimates) and above.There are no adequate and well-controlled studies inpregnant women. SALAGEN Tablets should be usedduring pregnancy only if the potential benefit justifiesthe potential risk to the fetus. Nursing Mothers It is not known whether this drug isexcreted in human milk. Because many drugs areexcreted in human milk and because of the potentialfor serious adverse reactions in nursing infants fromSALAGEN Tablets, a decision should be made whetherto discontinue nursing or to discontinue the drug, takinginto account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatricpatients have not been established. Geriatric Use Head & Neck Cancer Patients: In theplacebo-controlled clinical trials (See Clinical Studies section) the mean age of patients was approximately58 years (range 19 to 80). Of these patients, 97/369(61/217 receiving pilocarpine) were over the age of 65years. In the healthy volunteer studies, 15/150 subjectswere over the age of 65 years. In both study populations,the adverse events reported by those over 65 yearsand those 65 years and younger were comparable.Of the 15 elderly volunteers (5 women, 10 men), the5 women had higher Cmaxs and AUCs than the men.(See Pharmacokinetics section.) Sjogrens Syndrome Patients: In the placebo-controlledclinical trials (See Clinical Studies section), the meanage of patients was approximately 55 years (range 21to 85). The adverse events reported by those over 65 yearsand those 65 years and younger were comparableexcept for notable trends for urinary frequency, diarrhea,and dizziness (See ADVERSE REACTIONS section).

CLINICAL STUDIES SECTION.


C LINICAL STUDIES Head & Neck Cancer Patients : A 12 week randomized, double-blind, placebo-controlledstudy in 207 patients (142 men, 65 women) was conductedin patients whose mean agewas 58.5 yearswith a range of 19 to 77; the racial distribution wasCaucasian 95%, Black 4%, and other 1%. In thispopulation, a statistically significant improvement inmouth dryness occurred in the 5 and 10 mg SALAGEN Tablet treated patients compared to placebo treatedpatients. The 5 and 10 mg treated patients could notbe distinguished. (See Pharmacodynamics section forflow study details.) Another 12 week, double-blind, randomized, placebo-controlledstudy was conducted in 162 patients whosemean age was 57.8 years with a range of 27 to 80; theracial distribution was Caucasian 88%, Black 10%, andother 2%. The effects of placebo were compared to 2.5 mgthree times a day of SALAGEN Tablets for 4 weeksfollowed by adjustment to 5 mg three times a day and10 mg three times a day. Lowering of the dose wasnecessary because of adverse events in 3 of 67 patientstreated with 5 mg of SALAGEN Tablets and in 7 of 66patients treated with 10 mg of SALAGEN Tablets. After4 weeks of treatment, 2.5 mg of SALAGEN Tabletsthree times a day was comparable to placebo in relievingdryness. In patients treated with 5 mg and 10 mg ofSALAGEN Tablets, the greatest improvement in drynesswas noted in patients with no measurable salivary flowat baseline. In both studies, some patients noted improvement in theglobal assessment of their dry mouth, speaking withoutliquids, and a reduced need for supplemental oral comfortagents. In the two placebo-controlled clinical trials, the mostcommon adverse events related to drug, and increasingin rate as dose increases, were sweating, nausea,rhinitis, diarrhea, chills, flushing, urinary frequency, dizziness, and asthenia. The most common adverseexperience causing withdrawal from treatment wassweating (5 mg t.i.d. 1%; 10 mg t.i.d. =12%). Sjogrens Syndrome Patients: Two separate studieswere conducted in patients with primary or secondarySjogrens Syndrome. In both studies, the majority ofpatients best fit the European criteria for having primarySjogrens Syndrome. [Criteria for the Classificationof Sjogrens Syndrome (Vitali C, Bombardieri S,Moutsopoulos HM, et al: Preliminary criteria for theclassification of Sjogrens Syndrome. Arthritis Rheum.1993; 36:340-347.)] A 12-week, randomized, double-blind, parallel-group, placebo-controlled study was conducted in 256 patients(14 men, 242 women) whose mean age was 57 yearswith a range of 24 to 85 years. The racial distributionwas as follows: Caucasian 91%, Black 6%, and other 3%. The effects of placebo were compared with those of SALAGEN Tablets 5 mg four times a day (20 mg/day)for 6 weeks. At 6 weeks, the patients dosage wasincreased from 5 mg SALAGEN Tablets q.i.d. to 7.5 mgq.i.d. The data collected during the first 6 weeks of thetrial were evaluated for safety and efficacy, and thedata of the second 6 weeks of the trial were used toprovide additional evidence of safety. After 6 weeks of treatment,statistically significantglobal improvement of dry mouth was observed comparedto placebo. Global improvement is defined as ascore of 55 mm or more on a 100 mm visual analoguescale in response to the question, Please rate yourpresent condition of dry mouth (xerostomia) comparedwith your condition at the start of this study. Considerthe changes to your dry mouth and other symptomsrelated to your dry mouth that have occurred since youhave taken this medication. Patients assessments ofspecific dry mouth symptoms such as severity of drymouth, mouth discomfort, ability to speak withoutwater, ability to sleep without drinking water, ability toswallow food without drinking, and a decreased use ofsaliva substitutes were found to be consistent with thesignificant global improvement described. Another 12 week randomized, double-blind, parallel-group,placebo-controlled study was conducted in 373 patients(16 men, 357 women) whose mean age was 55 yearswith a range of 21 to 84. The racial distribution wasCaucasian 80%, Oriental 14%, Black2%, and 4% ofother origin. The treatment groups were 2.5 mg pilocarpinetablets, 5 mg SALAGEN Tablets, and placebo. All treatmentswere administered on a four times a day regimen. After 12 weeks of treatment, statistically significantglobal improvement of dry mouth was observed at adose of 5 mg compared with placebo. The 2.5 mg(10 mg/day) group was not significantly different thanplacebo. However, a subgroup of patients with rheumatoidarthritis tended to improve in global assessmentsat both the 2.5 mg q.i.d. (9 patients) and 5 mg q.i.d.(16 patients) dose (10-20 mg/day). The clinical significanceof this finding is unknown. Patients assessments of specific dry mouth symptomssuch as severity of dry mouth, mouth discomfort, abilityto sleep without drinking water, and decreased use ofsaliva substitutes were also found to be consistent withthe significant global improvement described whenmeasured after 6 weeks and 12 weeks of SALAGENTablets use.

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY Pharmacodynamics : Pilocarpine is a cholinergicparasympathomimetic agent exerting a broad spectrumof pharmacologic effects with predominant muscarinicaction. Pilocarpine, in appropriate dosage, can increasesecretion by the exocrine glands. The sweat, salivary, lacrimal, gastric, pancreatic, and intestinal glands andthe mucous cells of the respiratory tract may be stimulated.When applied topically to the eye as a single dose itcauses miosis, spasm of accommodation, and maycause a transitory rise in intraocular pressure followedby a more persistent fall. Dose-related smooth musclestimulation of the intestinal tract may cause increasedtone, increased motility, spasm, and tenesmus. Bronchialsmooth muscle tone may increase. The tone and motilityof urinary tract, gallbladder, and biliary duct smoothmuscle may be enhanced. Pilocarpine may have paradoxicaleffects on the cardiovascular system. The expectedeffect of a muscarinic agonist is vasodepression, butadministration of pilocarpine may produce hypertensionafter a brief episode of hypotension. Bradycardiaand tachycardia have both been reported with use ofpilocarpine. In a study of 12 healthy male volunteers there was adose-related increase in unstimulated salivary flowfollowing single 5 and 10 mg oral doses of SALAGENTablets. This effect of pilocarpine on salivary flow wastime-related with an onset at 20 minutes and a peakeffect at 1 hour with aduration of 3 to 5 hours (See Pharmacokinetics section). Head & Neck Cancer Patients: In a 12 week randomized,double-blind, placebo-controlled study in 207 patients(placebo, N=65; 5 mg, N=73; 10 mg, N=69), increasesfrom baseline (means 0.072 and 0.112 mL/min, ranges-0.690 to 0.728 and -0.380 to 1.689) of whole salivaflow for the 5 mg (63%) and 10 mg (90%) tablet,respectively, were seen 1 hour after the first dose ofSALAGEN Tablets. Increases in unstimulated parotidflow were seen following the first dose (means 0.025and 0.046 mL/min, ranges 0 to 0.414 and -0.070 to1.002 mL/min for the 5 and 10 mg dose, respectively).In this study, no correlation existed between theamount of increase in salivary flow and the degree ofsymptomatic relief. Sjogrens Syndrome Patients: In two 12 week randomized,double-blind, placebo-controlled studies in 629 patients(placebo, N=253; 2.5 mg, N=121; 5 mg, N=255; 5-7.5 mg,N=114), the ability of SALAGEN Tablets to stimulatesaliva production was assessed. In these trials usingvarying doses of SALAGEN Tablets (2.5-7.5 mg), therate of saliva production was plotted against time. AnArea Under the Curve (AUC) representing the totalamount of saliva produced during the observationinterval was calculated. Relative to placebo, an increasein the amount of saliva being produced was observedfollowing the first dose of SALAGEN Tablets and wasmaintained throughout the duration (12 weeks) of thetrials in an approximate dose response fashion (See Clinical Studies section). Pharmacokinetics: In a multiple-dose pharmacokineticstudy in male volunteers following 2 days of 5 or10 mg of oral pilocarpine hydrochloride tablets given at8 a.m., noontime, and 6 p.m., the mean eliminationhalf-life was 0.76 hours for the 5 mg dose and 1.35 hoursfor the 10 mg dose. Tmax values were 1.25 hours and0.85 hours. Cmax values were 15 ng/mL and 41 ng/mL.The AUC trapezoidal values were 33 h(ng/mL) and108 h(ng/mL), respectively, for the 5 and 10 mg dosesfollowing the last 6 hour dose. Pharmacokinetics in elderly male volunteers (N=11)were comparable to those in younger men. In fivehealthy elderly female volunteers, the mean Cmax andAUC were approximately twice that of elderly malesand young normal male volunteers. When taken with a high fat meal by 12 healthy malevolunteers, there was a decrease in the rate of absorptionof pilocarpine from SALAGEN Tablets. Mean Tmaxs were 1.47 and 0.87 hours, and mean Cmaxs were 51.8 and 59.2 ng/mL for fed and fasted, respectively. Limited information is available about the metabolismand elimination of pilocarpine in humans. Inactivationof pilocarpine is thought to occur at neuronal synapsesand probably in plasma. Pilocarpine and its minimallyactive or inactive degradation products, including pilocarpicacid, are excreted in the urine. Pilocarpine does notbind to human or rat plasma proteins over a concentrationrange of 5 to 25,000 ng/mL. The effect ofpilocarpine on plasma protein binding of other drugshas not been evaluated. In patients with mild to moderate hepatic impairment(N=12), administration of a single 5 mg doseresultedin a 30% decrease in total plasma clearance and adoubling of exposure (as measured by AUC). Peakplasma levels were also increased by about 30% andhalf-life was increased to 2.1 hrs. There were no significant differences in the pharmacokineticsof oral pilocarpine in volunteer subjects (N=8)with renal insufficiency (mean creatinine clearances25.4 mL/min; range 9.8 - 40.8 mL/min) compared tothe pharmacokinetics previously observed in normalvolunteers.

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS SALAGEN Tablets arecontraindicated in patients with uncontrolled asthma, known hypersensitivity to pilocarpine, and when miosisis undesirable, e.g., in acute iritis and in narrow-angle(angle closure) glaucoma.