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Progesterone Heragest® 200 mg Soft Gelatin Capsules Progestogens [ATC Cod - 030A FORMULATION Each soft gelatin capsule contains: Progesterone BP (Natural, Micronzed), 200m PHARMACOLOGIC CATEGORY Progestogens (ATC Code ~ G03DA) PRODUCT DESCRIPTION Progesterone (Heragst) 200 mg Saft Gelatin Capsules a crear, ol, soft gelatin capsule containing a pale yellow oy past. CLINICAL PHARMACOLOGY Phaimacodynamies Progesterone is a hormone produced inthe ovaries (specifically the corpus Iutaum), the adrenal glands and in the placenta during pregnancy. It acts on the ‘endometium by converting the proeating phase tothe secretory phate Progesterone capable fining anormal ful secretory endomlsium andin pvticul, ‘estagens, antestrgenc,sightly antiandrogen, and antaldosterone eects Pharmacokinetics Microniaed progesterone is absorbedinthe gastrointestinal tract. After oral administration of2 capsules (each capsule contains 200 my progesterone) of progesterone in healthy volunteer, an increase in pla progesterone levels fo a maximum concentration of 13.8 ng 2 2.9 ng in 2.2 + 14 hours wat observed, The ‘elimination hae observed was 168 = 23 hours. Although there were interindividual variations, the indivkual pharmaooKlele characteristics wore maintained over several monte, ldlcatng predietable responses tothe drug. Approximately 96 to 99% of progesterone is bound to serum proteins, primal to serum abumin(S0to 54%) and tanscorin (49 0 48%) Progesterone fs mataalized primary by the Wives The main plasma metabolites ate 20a hydrony-A 4a-prenclone and Sa-diydrageterone. Some progesterone metabolites are excreted inthe bile an these maybe conjugated an further metabolized in te gut via reduton, dehyronyation and epimerization, The maln plasma nd urinary metabolites are similar to those found during the pysilogical secretion tthe corpus lteum. Progesterone isoimiatad in the urine (85%) inthe form of giycurceonjugsted matabottes, mainly 8a, 89-pregnanediol oregnandil INDICATIONS. Infertility and Preumaney ‘Provide tal suppor in luteal phase defects in threstened/ecurent abortion + Prevent preterm delivery tea phase insutfcteney. * Progecerone challenge tet in oeondary amenorrhea * Oystuntional uterine bleaing (DU) + Menstrual rreguaies due to dysovultion or anovuation + Pramenstual syndrome + Foreystc mastopathy + Dyamenorea + Pramenopause Postmenopausal wome + Prevation of endometrial hyperplasia in postmenopausal women with intact uterus who ar recehing estrogen as hormone replacement therapy DOSAGE AND MODE OF ADMINISTRATION For oral administration, a directed bya pysctan ‘ORAL ADMINISTRATION Progesterone shoul be taken at bedtime. Oo aafaminster with food. In women wo experince ditficully swallowing the capsules, tke t ‘water il in standing position capsules with alas of Thaleaton ‘Watral Mironized Progesterone Oral bose “Treated abortonecurent abortion wth asa phase dteet 200 10 60019 daly 200 mg every 6 to 8 hous dapending on acute phase then supporting Freon titey dose of 600 mg/day divided ino 8 doses uni 36 weak of pregnancy Progesterone challenge lst in secondary anenortbea £00 mg aly at bedtime for 10 days Dystnctional urine tleding Menstrual eragutrites due to dysouuation a anowaation | 200 mg once dally tom 17 day ofthe cycle for 10 days Pramenstualsydrome, Fitzy mstopty Djemenantes, Pemonopase 209 409 ap ay a fo 10 day (ly ening ote revniion of eadomaral pepiasan pasinenopausal women wit ints tas whe are receiving estrogen as hormone replacement therapy 200 mg at beste for 12 days Sequential per 28 day eye (as deced ya physician ‘CONTRAINDICATIONS + Hypersnotity o progesterone orto any ingredient in te prot +I patents to peanut: th precuctcotins part (rachis) ot * Ace Wee esse, especialy of the cbstuctve type *Vistory a nawn osuspectdesroge-dependent or progestin dependent magnet neoplasia (breast cancer o endometrial cancer + Unclagrossd abnormal gant! bleedng * Atv or pct istry of areal trombcembals esas (¢.9, stoke, myocar farton coronary eat dese) * classical migrine * Cerebral hemorage *Actveo past history of confmed venous trombaembasm (deep venous thrombosis or pulmonary embolism) or cv hrembophitits + Paris or complet ss of ision de to eptthimi excl csessa * Missed orincarrpete sborton +t intended or regancy et * Porphyria ‘WARNINGS ANO PRECAUTIONS ‘General Progestins are usualy coadminstered th estrogens. Some the formation inthis econ pening to combine estrogen progestin therapy may thereto not analy to proest-ony therapy. Physcan dlcrton aed. Estrogen Piss Progestin in Menopausal Hormone Therapy Endometria\ Hyperplasia Estrogen, 6. single systemic agent, appropriate in women after hysterectomy. Oterwis, ction of micronized progesterone/progestogen s required for endometral protection. Estiogens plus progestin therapy shoud nt be ust forthe prevention of cardiovascular disease or dementia, Progestogens are not alike with regard to potential adverse metabolic foes, cognitive tects or assocatd br therapy Micronized progesterone or dyrogesterone used with estradiol may be associated wit a beter safety pote than synthetic progestins wih apart beast cancer and ‘eardiovaseuar risk. Physical Examinations “+ Patents shouldbe assessed prior to (and at regular intervals erate taking hormone replacement therapy (HRT). Physical examination (Ineuding spec aetion to the breast and pelic organs) and a Pap smear should be done. This should be guided by personal and family medical history and by the Containdctions and wamings of this product. + Endomettil biopsy should be done when indeated. Baseline tests should Include mammography, measuremens of blood glucose, eacium, tigheeties, cholesteral, and iver function tests, “The istfollow-up examination shouldbe dane within 9 o 6 months ate ntition of treatment to aesess response to treatment. Thereafter, examinations should bbe mate at intervals ofa kast once a year. Appropriate Investigations shouldbe arranged at regular interais determined by the physician. “+ Patents are encouraged to practice frequent seferamiation ofthe breasts. Stroke ‘Te risk of Ischemic stroke nas bet shown to be Increased curing the frst year of treatment wth continuous-comblned conjugated estrogens (0.625 mq) and Iedroryprogesterone cesta (2.5 ma) in postrenopaussl vemen (50 to 79 year od) compared to those receiving placebo. Estrogen plus progestin therapy should be ‘continued immedatey should a stoke acur or be expected ‘coronary Artery Disease (CAD) Randomized controled tals have shown no evidence of earslovascular bene vith the use of contnuous-combined conjugated estrogens ane medroxyprogesterone ‘ceats, This wes demonstrated in tha Women's Heath ntatve (WH) and Heat and estroganprogestn Replacement Study (HERS) which showed a possbole Increased risk of cardiovascular morbidity in the fist year of use with no overall benefit, High Blood Pressure ‘Monitor biood pressure in women using HR. Elevation of load pressure has teen observed inpatients using HAT. This elevation in blood pressure shouldbe vestigated In proviously normotensive or hypertansive patients. n such cases, HAT may hav o be dlscontnuad Venous Tiroraboembolism (VTE) -Aigher relative risk of developing VTE (ie, deep vein thrombosis or pulmenary embolism) i observed wth the use of estrogen or estrogen progesterone HRT. Persona history or family history, severe obesity (Dody mass Index, BM >G0 kgf), age end smoking ere the generally recognize factors for VTE Prolonged immobilization, major truma or majot surgery may temporarily increase the risk of VTE. As with al postoperative pallens, sttetion should be given to prophylactic measures to prevent VE aftr surgery. HRT should be temporary stopped 4 to 6 weeks earl (i possible) in instances where prolonged immobilization is ely to follow elective surgery, particularly abdomial surgery cr orthopedic surgery tothe lowe ims. Do not restart therapy unt the patent is completly mobiize, ‘Alco close supervision fs alee in patent with varicose veins. Progesterone shoul be discontinvd in case VTE is suspected or develops ate ination of therapy. lua Retention Use progesterone with cautonin patents wit conatons that might be aggravated by tua retention (eg, hypertension, cardiac lease, eral disease eplepy, migraine, ast); in pallens wth 2 history of depression, dlabetes, mild to moderate hepate dysfunction, migraine or photosenitvty and in breastfeeding mothers. ‘tucose and Lipid Metabolism A signticant percentage of pr and postmenopausal patients taking progestins has been shown to develop worsening of blood glucose tolerance and ipid metabolism ‘Glosely observe diabetic patents or tose witha predisposition to dabetes to detect any alterations in carbohycrate oF lipid metabolism, especialy In tgceride blood love cancer risk when combined with systemic estrogen {aleium and Phosphorus Metaboliem ‘The prolonged use of estrogens, wth or without progestins, iuences calsum and phosphorus mtabolm. Patients with metabole and magnant bone diseases associated with hypereleaia and paints wit renal insufficiency should uoe estrogens (with or without progestine) wth caution. Familia Hyperlipidemias or Porphyria ‘Women wit femal hyperlipdemias or porphyria nee special suvelnce,Adctiona ipid-owering measures are recommend as appropiate, Breast Cancer Its suggested that estrogen plus progestin therapy may cause a mild increase inthe risk of breast cancer. Athough i isnot known whether this also occurs with ‘concutent progesterone therapy aliens should reer to the prescribing information forthe co-rescribed estrogen fot nfrmation about the risk of breast cancer Etrogens wth or without progestin isnot recommended tobe vento vlomen wih exisng breast cance oF those with a history ofthe disease. Caution advised in prescribing estrogens with or without progestins in women with mown rik factors associated with the development of breat cancer such as etzong farily history of breast cancer (fist deoree relative) or who present abreast condition wi an increased isk (abnormal mammograms andor atypical hyperplasia al breast biopsy) Nuliparty, obesity, early menarche, late age a fst ful erm pregnancy and at menopause should also be evaluated for these are known factors forthe development of breast cance, ‘An inoease in cbnormal mammograms has been observed with the use of progestin plus estrogen therapy. Further evaluation is required to contin these results. ll ‘women should receive yeary breast examinations (by a healthcare provider) and perform monthly breast sell-examinaions. Marimography examinations should be ‘scheduled based on patient age, rs factors and prior marnmogram results ‘The degree of association between breast cancer and menopause hormone therapy (MT) remains controversial, Most long-term studies reflect the use of one specie Combination of oral estrogen and progestogen and suggest a possibe Increased risk wih increasing duration Thee studies suggest that microns progesterone or ‘dydrogecerone cout be associated wit a lower rick than synthetic progectogen. A large European observatlonal study euggested that micronized progesterone or ‘yérogesterone used in association with oral or percutaneous estradiol may be assoiatd wit a better risk profil for breast cance tan synthete progestogens. A ‘case-control study from France also showed a lower level of sk with progesterone than synthetic progestogens. ‘The increased risk of breast cancer 18 primary associated wih the addition of a synthetic progestogen to estrogen therapy (conjugated estrogen and mearoxyprogesterone acetate continuous combined therapy) and related tothe duration of use. The sk maybe lower with micronized progestrone or dydrogesterone ‘than wit 2 synthetic progestogen. The risk of breast cancer atributabe to MT is sal and the risk decreases progressively after treatments stopped. Endometrial Cancer ‘When estrogens are administered alone or for prolonged periods, the isk of endomatra hyperplasia anc carcinoma Is increased Progestins may cause breakthrough bleeding and spotting Heeding during the irs months of trestment. these symptoms ar stil present after € months of treatment, it starts beyond that time oi continues aftr treatment has been discontinued, advise patients to report to their doctor and be referred for gynecological investigation. Insuch cases, agnostic measures (eg, endometrial Biopsy or curettage) must be undertaken to rule out the possibilty of uterine malignancy and treatment shouldbe re-evauated in these paints. The adaion of progesterone to estrogen-only HRT fr 10 or more days per eyce grea reduces this risk ln non hysteectomized women. Ovarian Cancer ‘Some epidemiological tudes have shown that long-term use (atleast 5 years or mors) of estrogen plus progestin and estrgerronly HRT products has been associated with an increased risk of ovarian cancer. However, it uncertain whather long-term use of combined HRT confers a diferent risk than estogen-only products, Cerobrovascuar Insuiciency Discontinue therapy if patient experiences visual disturbances, classical migraine, transient aphasia, paralyis,or loss of consciousness during therapy. Patients with a previous history of classical migraine and who develop arecurenceor worsening of migraine symptoms shouldbe re-evaluated, Dement ‘Although some evidence xt trom the WHI rl of increased risk of probable dementia in women who stat using continuous combined conjugatd estrogen and medroxyprogesterone acetate after 65 years od, ts not known whether these findings apely to younger postmenopausal women or other HRT products. Pre-existing Mental Depression Use progesterone wih caution in patents with pre-existing mental daprcsion. Progesterone shouldbe discontinued if depresion recurs toa serious dagre during therapy. Viva Elects Retina vascular thrombosis has ocurred inpatients receiving estrogen. Estrogen plus progesterone therapy should be withheld i unexplained, sudden or gradu partal ‘or complete loss of vision, proptoss or aiplopa ppillecera, retinal vascular lesions, of migraine occurs. Appropriate and therapeutic measures shouldbe instituted in ‘thee patients. Discontinue permanent i amination reveals papiledema or retinal vascular lecons. Carcinogenicity, Mutagenesis, Impairment of Fertility Progesterone, when implanted into female mice, produced mammary earcnomes, ovarian granulosa cell tumors and endometa stromal carcinomas. Long-term inte rscular (IM) injections in dogs produces nodular hyperpas.a and benign and malignant mammary tumors. Rats that were gen subcutaneous (SC) or IM injections ‘of progestrone and wer previously treated wth chemical carcinogen had a ower lene period and an increased incidence of mammary tumors, Progesterone hes not ben tested for careinogenieity in animals by the oral out of administration. In wir studies, progesterone di not show evidence ot genotoxic for point mutstions or for chromosomal damage nin vive studies, however, chromosomal damage was present in mice at orl doses of 1600 mg/kg and 2000 mg/g Inhibition of ovulation has Been shown ina numberof species when progesterone ks administered ‘exogenously, Impaled frit s expected when progesterone Is given a high doses and fran axtended duration ntl treatment stopped {Etecis onthe Ability 1 Drive and Use Machines Progesterone use may result in transient and occasional somnolence or dizziess/drowsiness which usually occurs 1 to 4 hous aftr ingestion. This condition may be aggravates when progesterone is administered with food, Patients should be warned that visual symptoms may make activites such as ding or operating machiery tore hazardous tan usual under condtions of vrable ighting, Taking the capsules at bectime should reduce these elects curing the dy INTERACTIONS WITH OTHER MEDICAMENTS. Drugs Inducing Liver Enzymas (e.9., carbamazepine, griseollvn, barbiturates, hydantoin, meprobamates, phesylbulazone, or ifampicia): The metabolism of Progesterone may be enhanced and ts activity reduced by compounds that induce liver enzymes. (jlechcome P45D Inhibitors Ketoconazole (an nibtor ct CYP4SO 2s) ntbedthe metabo of progesterone. An increase nthe Bisvalabilty of progesterone may be expected however, the relevance of tis In vitofnding is unknown, ‘The bioavetbity of medroxyprogesterone acetate may be sigiicanly reduced when coneomvtanty administered with aminoglutethimide. I unknown wheather tis interaction occurs with progesterone. ‘Anidiabeic Agents: Progesterone can decrease glucose tolerance and therefore an adjustment in the anabeic dosage may be require, ‘Bromocriptine: Bromocsiptine ibis prolactin. This may interfere wth te elects of progesterone resting in 2 decreased progesterone action. Cielesporin: Progesterone ray inhibit ilospocin metabo leading to increseed plasma eieleapein concentrations. ‘Conjugated Esirogans: administration of conugated estrogens and progesterone rested in an incase in ttal estrone concentrations and total equincancentatons ‘and a decrease in culating 178 estradiol concentration. The half ofthe conjugated estrogens was sila wth coadminstration of progesterone. ‘Herbal Producis: Some herbal products such a St John's Wort may reduce the effet of progesterone. Food: Food increases the bioavailability of progesterone relative to a fasting state when administered a a dose of 200 mg, Progest (Gra vals with no effect on Tr ‘The following ieboratory resus may be alereé by the use of estrogen and progestin therapy: Increase sultobromophthalen retention and other hepatic function tests, Coagulation tests (noease in prothrombin factors Vi, Vl, IX, and x, pregnanedol determination, thyroid function (Inereases in PBI, and butanol extractable protein bound iodine and decrease in 3 uptake value) ‘STATEMENT OW USAGE FOR HIGH RISK GROUPS Pregnancy: Pregaaney Category 8. Projeserone may delay spontaneous abortion cf fertized detective ova because of thelr Merine-relaant effects. Also, the commen ‘ause of abortion in most women is detective ovum which progesterone could not be expectd to ifiuence ‘Tere is evidence of potential adverse effects onthe fetus when the drug is administered during the ist 4 months of pregnancy. Prescription of progesterone beyond the fist vimester of pregnancy may reveal gravid cholestasis. case of cle alse was reported, When used or unapproved uses, ae cases of fetal death (causality not established) nave been reported Lactation: Progesterone fs excreted in human mik Since the possible fects of progesterone on the breastfeeding infant have not been determined, caution should be ‘exercised en progesterone is administered to breastieading mothers. Peaitie: Progesterone isnot intends or use in cidren. No cna studies npedare popuation have been conducted. (Geriatric: othe WHI estrogen plus progestin subetudy there was a higher relative ick of nonfatal stroke and invasive beast cance in women >65 years old. Tere was ‘an increased rik of developing probable dementia in WHIMS estrogen pls progetin ancillary study in women aged €5 to 79 years, However ro suicent numbers of ‘efarc wemen are invlvedin clinical studies to deterrine i there sa difference inthe response of women over 65 years from the younger subjects to progesterone. 1 signticantly increases AUC and ‘epatie Impairment: Tha eect ot hepatic impairment cn the pharmacokinetics of progesterone has not been studied. However, since sexual hormones are metabolize nthe liver, progestrone sould be usee with caution in these paints. Liver function tests shouldbe done regularly in patlnts who ae suspected of having hepatle disease. ‘Renal impairment: The efecto renal impairment onthe pharmacckinetics of progesterone has not been stud, [UNDESIRABLE EFFECTS: Iafectons and ffestations: Upper respiratory Infection, vi infection Neoplasms, beniga, malignant and unspeciied (ine! cysts and polyps} Breast carcinoma Blood and lymphatic system disorders: Jaundice mune system disorders: Anaphylxisfnaphylatc rection, angioedema, asthma, erythema matte, erthema nadosum, sil edema, hypersensitivity, urticaria Endocrine serdar: Wrsutem, mascuinzation o emule fetus, ovarian hyperstimulation syndrome ‘Metabolism and auton disorders: Changes in appette, changes in body weight, edema, uid retention, sodium retnon Pyehiatric disorders: Aggression, anxety)worry, contusion, depersonaization, disorientation, drowsiness, dysarthialsured speech, emotional lability, impaired concentration, soma, mental depression, mood change, nervousness, somnolence, stupor, suieial ideation, treat tightness [Nervous system dizorders:kggravation of migrsine episodes, convulsion, depressed level cf eanecicusness, duly waking/got dstrbence, diziness,hesdache, loss of Consciousness, neuris, paresthesia, sedation, vertigo ye disorders: Blurred vision, contact len intolerance, diplopia, neuo-ceuar lesions disturbances Ear and labyrinth disorders:Tnntus Cardiac disorders: Chest pain, coronary thrombosis, dyspnea, plptaton, tachycardia Vaseular disorders: Crcuiaory collpse, hot flush, hypertension, hypotension, syncope (with and without hypotension), thromboambolic disorders, thrombophlebitis, ‘tansantsehemic attack (TA), vanows thrombosmbotsm (Le. deep le oF pale vanous thrombosis or pulmonary embolism) Respiratory, thoracic and mediastna! disorders: Choking, cough, nisopharyngis Gastrointestinal disorders: Abdominal discomont (cramps, pressure, bloating, pain), acute pancreas, constipation, dare, dysphagia, gastrointestinal disturbance, nausea, swollen tongue, vomiting Hepatobiliary disorders: Asymptomatic impaired Wer function, cholestasis, cholestatic hepatitis, cholestatic jaundice, gallolader disorder, hepatic alr, hepatic necrosis, hepatitis, nepatacellar Iver disease (ar) Skin and subcutaneous tssue disorders: Acne, chloasma (melasma), e¢zems, halls (alopecia). hemorrhagic eruption, prurtus, rash Iuseulesteteia and comecive iseue disorder: Krtnagia, back pan, muscle cramp, musculoskeketal pn. ‘Renal and urinary disorders: Cysts, dys, urinary problems, urinary tract nection Pregnancy, puerperium and perinatal conditions: Spontaneous abortion ‘Reproductive system and breast disorders: Atered menstrual cyle or iregular menstrual Needing, breast discomfort, breast pain, beast tenderness, change i bdo, changes in cervical erosion and amount of ceva secretion, dysmenorrea, dyspareunia, endometrial carcinoma, endometrial hyperplasia gynecomastia, heavier menses (imenorthags), Mypespadia, menstval corde, metormagis, ovarian cys, perineal pain, promenstrual Ike syndrome, rescthation of endometrisis, shortening ofthe ‘menstrual cyte or breakthrough beedingspoting, uterine hemorrhage, vagina discharge, vaginal dryness, vaginal Reng, vaginal mycosis Congenita, amilial and genetic disorders: le, cet palate, congenital heat disease (ineuding ventricular septal defect and patent ductus arteriosus) General disorders and administration ste conditions: Fatigue, ising abnoral, feng drunk, fetal death, fever, italy lethargy, malas, night sweals, pan, peripheral sweling Investigations: Atered coagulation test, altered lipid protie, breast excisional Biopsy, decreased ghcose tolerance, dereased weight Increased blood glucose ev, Increase bloodpressure, increased ner function test alanine aminotransferase, aspartate aminotansfrase, gamma-Gltamy/ transferase), increased weight Surgica| and medical procedures: Need for cholaystectory ‘OVERDOSE AND TREATMENT ‘The toy of progesterone fs very low. Symptoms that may occur Include nausea, vornting, somnclence,ezziness,euphora, or dysmenorhea. Appropriate suppertve ‘measures should be performed and progesterone shouldbe discontinued in cases of overdose. ‘STORAGE CONDITIONS ‘Store at temperatures not exceeding 30°C. Protect rom heat, ght, and excess hur Koop the product out of reach and eight children Stor in orginal packaging [ADVERSE DRUG REACTION REPORTING STATEMENT For suspected adverse drug reaction, seek medcal attention immediately and report to the FOR at wwwfdagovph AND Unlab at (4632) 868-1000 or roductsafety@unla.com.ph. By reporting undesirable fects, you ean hep provide more information onthe safety ofthis medicine. AVAILABILITY Clear PVC Blister Packx 10% (Box o! 100%) ‘cauTioN Foods, Drugs, Dovees and Cosmetics Act prohibits dispensing wthout prescription, Date of Revision of the Package Inset: Apr 2017 retinal thrombosis, optic neu). steepening of the corneal curvature, visual Manutatured by: ‘Stet-Gene Lie Stlencs (P) Lid. No 45 Mangalam Main Road, Mangalam Vilage ‘Vlanur Commune, Puducherry ~ 605110, Inia Imported and Distbute by LUNILAB, Ine. No 66 Unitod strest, Mandaluyong city Metro Manila, Philippines DR-xvasoat Date of Fist Authorization: June 2016 eg, IPOPHIL BiFis63571N08|

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