Zafrilla tablets 2mg, No. 28

• Endometriosis treatment.

Inside, regardless of the meal.
Before you start taking ZafrillaЃ, you must stop using any hormonal contraception. If necessary, contraception uses non-hormonal methods (for example, barrier).
It is possible to start taking ZafrillaЃ on any day of the menstrual cycle. The drug is taken 1 tablet per day continuously, preferably at the same time, if necessary with a small amount of liquid. The tablets should be taken regularly, regardless of vaginal bleeding. After the completion of taking the tablets from one package, start taking ZafrillaЃ from the next package, without taking a break in taking the drug.
In case of missed pills, vomiting and / or diarrhea (if this occurs within 3-4 hours after taking the pill), the effectiveness of ZafrillaЃ may decrease. In case of missing one or more pills, a woman should take only one pill at once, as soon as she remembers about it, then the next day, continue taking the pills at the usual time. If absorption of the drug is impaired due to vomiting or diarrhea, one tablet should also be taken.
The duration of the drug intake is 6 months. The decision on further therapy with dienogest is made by the doctor depending on the clinical picture.
Special patient groups
Adolescent girls under the age of 18
The use of the drug in adolescent girls under the age of 18 is contraindicated due to the lack of data on the efficacy and safety of dienogest in this age category.
Elderly patients (over 65 years old) There are no
reasonable indications for the use of ZafrillaЃ in elderly patients.
Patients with hepatic impairment
ZafrillaЃ is contraindicated in patients with severe liver disease - current or history (see section 'Contraindications').
Patients with renal insufficiency
There is no evidence of the need for dose adjustment in patients with impaired renal function.

1 tablet contains:
Active ingredient: dienogest (micronized) 2 mg.
Excipients: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, povidone-K25, crospovidone (type A), talc, magnesium stearate.

The use of ZafrillaЃ is contraindicated in the presence of any of the conditions / diseases / risk factors listed below, some of which are common to all drugs containing only a gestagenic component.

• Acute venous thrombophlebitis, venous thromboembolism (VTE).

• Diseases of the heart and arteries, which are based on atherosclerotic vascular lesions (including ischemic heart disease, myocardial infarction, cerebrovascular accident), currently or in history.

• Diabetes mellitus with angiopathy.

• Severe liver disease at present or in history prior to normalization of liver function parameters.

• Liver tumors (benign or malignant), current or history.

• Diagnosed hormone-dependent malignant diseases of the genital organs or breast, or suspicion of them.

• Vaginal bleeding of unknown origin.

• Hypersensitivity to dienogest or any of the excipients.

• Pregnancy and the period of breastfeeding.

• Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

• Age up to 18 years (due to the lack of data on the efficacy and safety of dienogest in this age group).

If any of these conditions / diseases / risk factors develop while using the drug, the drug should be stopped immediately.

Carefully

History of depression, history of ectopic pregnancy, arterial hypertension, chronic heart failure, migraine with aura, diabetes mellitus without vascular complications, hyperlipidemia, history of deep vein thrombophlebitis, personal and family history of VTE (see section 'Special instructions') ...

Trade name:

ZafrillaЃ

International non-proprietary name:

dienogest

Dosage form:

pills

Composition

1 tablet contains:
Active ingredient: dienogest (micronized) 2 mg.
Excipients: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, povidone-K25, crospovidone (type A), talc, magnesium stearate.

Description

Round, flat tablets of white or off-white color, beveled and engraved with УG93Ф on one side and УRGФ on the other side.

Pharmacotherapeutic group:

gestagen.

ATX code:

G03DB08

Pharmacological properties

Pharmacodynamics
Dienogest is a derivative of nortestosterone, characterized by antiandrogenic activity, accounting for approximately one third of the activity of cyproterone acetate.
Dienogest binds to progesterone receptors in a woman's uterus, having only 10% relative affinity for progesterone receptors. Despite its low affinity for progesterone receptors, dienogest has a potent progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.
Dienogest acts on endometriosis by suppressing the trophic effects of estradiol in relation to the autopic and ectopic endometrium, due to a decrease in the production of estrogens in the ovaries and a decrease in their concentration in plasma.
With prolonged use, it causes an initial decidualization of endometrial tissue with subsequent atrophy of endometrioid foci. Other pharmacological properties of dienogest, such as immunomodulatory and antiangiogenic, probably contribute to its suppressive effect on cell proliferation.
The advantage of dienogest over placebo for pelvic pain associated with endometriosis was demonstrated in 198 patients in a 3-month clinical study. Pelvic pain associated with endometriosis was assessed using a visual analogue scale (VAS, 0-100 mm). After 3 months of treatment with dienogest, a statistically significant difference from placebo was shown (? = 12.3 mm; 95% CI: 6.4-18.1; p <0.0001), as well as a clinically significant reduction in pain from baseline. (average decrease = 27.4 mm ± 22.9).
After 3 months of treatment, 37.3% of patients showed a decrease in the intensity of pelvic pain associated with endometriosis by 50% or more without a corresponding increase in the dose of additional anesthetic that they took (in the placebo group: 19.8%); 18.6% of patients experienced a 75% or more reduction in the intensity of pelvic pain associated with endometriosis without increasing the dose of additional pain reliever they were taking (placebo: 7.3%).
In the extended open phase of this placebo-controlled study, there was a sustained reduction in pelvic pain associated with endometriosis with treatment durations up to 15 months.
The results of the placebo-controlled part of the study were confirmed by the results obtained in a study with an active control group (taking a gonadotropin-releasing hormone (GnRH) agonist) for 6 months in 252 patients with endometriosis.
Three studies involving a total of 252 patients who received a daily dose of 2 mg dienogest demonstrated a significant reduction in endometriotic lesions after 6 months of treatment.
In a small study (n = 8 in each dose group), it was shown that dienogest at a daily dose of 1 mg after 1 month caused the development of anovulatory status. The study of the contraceptive effectiveness of dienogest in larger studies has not been conducted.
During the period of therapy with dienogest, there is a moderate decrease in the concentration of endogenous estrogens. There are currently no data from a long-term study of bone mineral density (BMD) and the risk of fractures when taking dienogest.
BMD was assessed in 21 adult patients before the start of treatment and after 6 months of using the drug; there was no decrease in the average BMD. After the same period of treatment with leuprorelin acetate (LA), 29 patients showed a decrease in BMD by 4.04% ± 4.84 (? between groups = 4.29%; 95% CI: 1.93-6.66; p <0 , 0003).
During the use of dienogest for up to 15 months, no significant effect of the drug on standard laboratory parameters, including hematology, blood chemistry, liver enzymes, lipids, and glycated hemoglobin, was observed.
In a 12-month study involving 111 adolescent patients, in 103 patients, the mean relative change in BMD of the lumbar spine (L2-L4 vertebrae) compared to baseline was 1.2%. 6 months after the end of treatment, within the framework of the period of continued observation, in the group of patients who had a decrease in BMD, this parameter was measured again, and the analysis showed an increase in the BMD level towards the initial indicator to a level of 0.6%.
Preclinical data from standard safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity do not indicate a specific risk to humans. However, it should be borne in mind that sex hormones can stimulate the growth of a number of hormone-dependent tissues and tumors.

Pharmacokinetics
Absorption
Dienogest is rapidly and almost completely absorbed after oral administration. The maximum plasma concentration of 47 ng / ml is reached approximately 1.5 hours after a single oral dose. Bioavailability is about 91%. The pharmacokinetics of dienogest in the dose range from 1 to 8 mg is dose-dependent.
Distribution
Dienogest binds to albumin in the blood plasma and does not bind to sex hormone binding globulin (SHBG), as well as to corticosteroid binding globulin (CSG). 10% of the total concentration of the substance in the blood plasma is in the form of a free steroid, while about 90% is nonspecifically bound to albumin. The apparent volume of distribution of dienogest is 40 liters.
Metabolism
Dienogest is almost completely metabolized mainly by hydroxylation to form several practically inactive metabolites. Based on the results of in vitro and in vivo studies, the main enzyme involved in the metabolism of dienogest is CYP3A4. Metabolites are excreted very quickly, so that the predominant fraction in the blood plasma is unchanged dienogest.
The metabolic clearance rate from blood plasma is 64 ml / min.
Withdrawal
The concentration of dienogest in blood plasma decreases in two phases. The half-life in the terminal phase is approximately 9-10 hours. After oral administration at a dose of 0.1 mg / kg, dienogest is excreted as metabolites by the kidneys and through the intestines in a ratio of approximately 3: 1. The half-life of metabolites by the kidneys is 14 hours. After oral administration, approximately 86% of the dose received is excreted within 6 days, with the main part being excreted in the first 24 hours, mainly by the kidneys.
Equilibrium concentration
The pharmacokinetics of dienogest does not depend on the level of SHBG. The concentration of dienogest in blood plasma after daily use increases by about 1.24 times, reaching an equilibrium concentration after 4 days of administration. The pharmacokinetics of dienogest after repeated use of the drug can be predicted on the basis of the pharmacokinetics after a single use.
Pharmacokinetics in special groups of patients
Patients with renal insufficiency
No pharmacokinetic studies of dienogest have been carried out in patients with impaired renal function.
Patients with hepatic impairment The
pharmacokinetics of dienogest in patients with hepatic impairment have not been studied.

Indications for use

• Endometriosis treatment.

Contraindications

The use of ZafrillaЃ is contraindicated in the presence of any of the conditions / diseases / risk factors listed below, some of which are common to all drugs containing only a gestagenic component.

• Acute venous thrombophlebitis, venous thromboembolism (VTE).

• Diseases of the heart and arteries, which are based on atherosclerotic vascular lesions (including ischemic heart disease, myocardial infarction, cerebrovascular accident), currently or in history.

• Diabetes mellitus with angiopathy.

• Severe liver disease at present or in history prior to normalization of liver function parameters.

• Liver tumors (benign or malignant), current or history.

• Diagnosed hormone-dependent malignant diseases of the genital organs or breast, or suspicion of them.

• Vaginal bleeding of unknown origin.

• Hypersensitivity to dienogest or any of the excipients.

• Pregnancy and the period of breastfeeding.

• Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

• Age up to 18 years (due to the lack of data on the efficacy and safety of dienogest in this age group).

If any of these conditions / diseases / risk factors develop while using the drug, the drug should be stopped immediately.

Carefully

History of depression, history of ectopic pregnancy, arterial hypertension, chronic heart failure, migraine with aura, diabetes mellitus without vascular complications, hyperlipidemia, history of deep vein thrombophlebitis, personal and family history of VTE (see section 'Special instructions') ...

Application during pregnancy and breastfeeding

Pregnancy
Data on the use of dienogest in pregnant women are very limited. In animal studies, reproductive toxicity, genotoxicity and carcinogenicity with the introduction of dienogest were not detected. The use of the drug during pregnancy is contraindicated due to the lack of the need for endometriosis therapy during pregnancy.
Breastfeeding period
Taking ZafrillaЃ during breastfeeding is contraindicated. Animal studies have shown that dienogest is absorbed into the milk of lactating animals. It is not known whether dienogest passes into human breast milk. It is necessary to resolve the issue of stopping breastfeeding or therapy with ZafrillaЃ.
The decision to stop breastfeeding or to stop taking ZafrillaЃ is made based on an assessment of the ratio of the benefits of breastfeeding for the child and the benefits of dienogest therapy for the woman.

Method of administration and dosage

Inside, regardless of the meal.
Before you start taking ZafrillaЃ, you must stop using any hormonal contraception. If necessary, contraception uses non-hormonal methods (for example, barrier).
It is possible to start taking ZafrillaЃ on any day of the menstrual cycle. The drug is taken 1 tablet per day continuously, preferably at the same time, if necessary with a small amount of liquid. The tablets should be taken regularly, regardless of vaginal bleeding. After the completion of taking the tablets from one package, start taking ZafrillaЃ from the next package, without taking a break in taking the drug.
In case of missed pills, vomiting and / or diarrhea (if this occurs within 3-4 hours after taking the pill), the effectiveness of ZafrillaЃ may decrease. In case of missing one or more pills, a woman should take only one pill at once, as soon as she remembers about it, then the next day, continue taking the pills at the usual time. If absorption of the drug is impaired due to vomiting or diarrhea, one tablet should also be taken.
The duration of the drug intake is 6 months. The decision on further therapy with dienogest is made by the doctor depending on the clinical picture.
Special patient groups
Adolescent girls under the age of 18
The use of the drug in adolescent girls under the age of 18 is contraindicated due to the lack of data on the efficacy and safety of dienogest in this age category.
Elderly patients (over 65 years old) There are no
reasonable indications for the use of ZafrillaЃ in elderly patients.
Patients with hepatic impairment
ZafrillaЃ is contraindicated in patients with severe liver disease - current or history (see section 'Contraindications').
Patients with renal insufficiency
There is no evidence of the need for dose adjustment in patients with impaired renal function.

Side effect

Adverse reactions (HP) more often occur in the first months after the start of therapy with ZafrillaЃ and decrease with continued treatment. Changes in the nature of bleeding are possible, for example, 'spotting' spotting, irregular bleeding, or amenorrhea. The most common HPs seen with dienogest are headache, breast discomfort, depressed mood and acne. In addition, in most patients receiving dienogest, the pattern of menstrual bleeding changes. During the first 90 days of dienogest therapy, the following types of menstrual irregularities were observed: amenorrhea, infrequent bleeding, frequent bleeding, irregular bleeding, prolonged bleeding.
Below are the HPs noted with dienogest.

Overdose

Serious overdose irregularities have not been reported.
Symptoms that may occur in case of an overdose: nausea, vomiting, 'smearing' spotting or metrorrhagia.
Treatment: there is no specific antidote, symptomatic treatment should be carried out.

Interaction with other medicinal products

The effect of other drugs on dienogest
Gestagens, including dienogest, are metabolized mainly with the participation of isoenzymes of the cytochrome P450 ZA4 (CYP3A4) system in the intestinal and liver mucosa. Therefore, inducers or inhibitors of CYP3A4 can affect the metabolism of gestagens.
The increased clearance of sex hormones due to the induction of enzymes can lead to a decrease in the therapeutic effect of dienogest, and also cause HP, for example, a change in the pattern of uterine bleeding.
Decreased sex hormone clearance due to enzyme inhibition can increase dienogest exposure and cause HP.
Substances that increase the clearance of sex hormones (decrease in effectiveness by induction of enzymes)
Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and herbal medicines containing St. John's wort (Hypericum perforatum). Enzyme induction is usually noted a few days after the start of therapy, the maximum induction is noted for several weeks and then may persist for 4 weeks after the cessation of therapy.
The effect of the CYP3A4 inducer rifampicin has been studied in healthy postmenopausal women. With the simultaneous use of rifampicin with a combination of estradiol valerate + dienogest, a significant decrease in the equilibrium concentration and systemic exposure of dienogest was noted. The systemic exposure of dienogest at equilibrium concentration, determined by the value of AUC (0-24 hours), was reduced by 83%.
Medicines with a variable effect on the clearance of sex hormones
When used simultaneously with sex hormones, many combinations of protease inhibitors and non-nucleoside reverse transcriptase inhibitors for the treatment of HIV infection and viral hepatitis C can increase or decrease the concentration of progestogen in the blood plasma. The cumulative effects of these changes in some cases may be clinically significant.
Medicines that reduce the clearance of sex hormones (enzyme inhibitors)
Dienogest is a substrate of the CYP3A4 isoenzyme of the cytochrome P450 system.
Concomitant use of highly active CYP3A4 inhibitors can increase the concentration of dienogest in blood plasma.
The simultaneous use of ketoconazole with a strong inhibitor of CYP3A4 enzymes led to an increase in the AUC value (0-24 h) of dienogest at the equilibrium concentration by 2.9 times. The simultaneous use of a moderate inhibitor of erythromycin increased the AUC (0-24 h) of dienogest at an equilibrium concentration by 1.6 times.
Effect of dienogest on other medicinal products
Based on data from in vitro inhibition studies,a clinically significant interaction of dienogest with other drugs metabolized by isoenzymes of the cytochrome P450 system is unlikely.
Note: To clarify possible interactions, please see the instructions for use of concomitant medications.
Interaction with Foods
Ingestion of food with a high fat content did not affect the bioavailability of dienogest.
Other types of interaction
The use of gestagens can affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, plasma concentrations of carrier proteins, for example, lipid / lipoprotein fractions, carbohydrate metabolism parameters, blood coagulation and fibrinolysis.
Typically, these interactions are within the normal laboratory range.

special instructions

Before starting to use the drug, pregnancy must be excluded. During the use of the drug, if contraception is necessary, patients are advised to use non-hormonal contraceptive methods (for example, barrier).
Fertility
Based on the available data, ovulation is suppressed in most patients with the drug. However, dienogest 2 mg is not a contraceptive pill.
According to available data, the physiological menstrual cycle returns to normal within 2 months after discontinuation of dienogest treatment.
¬еро¤тность наступлени¤ эктопической беременности выше у пациенток, принимающих с целью контрацепции препараты, содержащие только гестагенный компонент, по сравнению с пациентками, принимающими комбинированные пероральные контрацептивы. “аким образом, дл¤ женщин с внематочной беременностью в анамнезе или при непроходимости маточных труб следует оценивать соотношение пользы и риска перед применением диеногеста.
»зменение характера кровотечений
” большинства женщин применение диеногеста вли¤ет на характер менструальных кровотечений.
ѕри применении диеногеста возможно усиление маточного кровотечени¤, например, у женщин с аденомиозом матки и лейомиомами матки. ѕри т¤желом и продолжительном кровотечении возможно развитие анемии (иногда т¤желой). ¬ случае анемии следует рассмотреть вопрос об отмене препарата.
Ќарушени¤ кровообращени¤
¬ процессе эпидемиологических исследований показана недостаточно убедительна¤ взаимосв¤зь между применением монопрепаратов прогестагена и повышением риска инфаркта миокарда или тромбоэмболии сосудов головного мозга. ¬ большей степени риск сердечно-сосудистых и церебральных заболеваний св¤зан с возрастом, наличием артериальной гипертензии и курением. ” женщин с гипертензией риск развити¤ инсульта при приеме монопрепаратов прогестагена может незначительно увеличиватьс¤. ¬ отдельных исследовани¤х показано небольшое и статистически незначимое увеличение риска венозной тромбоэмболии (тромбоза глубоких вен, тромбоэмболии легочной артерии) при использовании монопрепаратов прогестагена. ќбщепризнанными факторами риска ¬“Ё ¤вл¤ютс¤ наличие ¬“Ё в анамнезе у пациентов или в семейном анамнезе (¬“Ё у брата/сестры или родител¤ в возрасте менее 50 лет), возраст, ожирение, длительна¤ иммобилизаци¤, серьезное оперативное вмешательство или обширна¤ травма. ¬ таких случа¤х следует прекратить прием диеногеста (не менее чем за четыре недели до плановой операции) и возобновл¤ть прием не ранее чем через две недели после полного восстановлени¤ двигательной активности.
—ледует учитывать повышенный риск развити¤ тромбоэмболии в послеродовом периоде. ѕри развитии или подозрении на развитие артериального или венозного тромбоза применение препарата следует немедленно прекратить.
ќпухоли
ћета-анализ 54 эпидемиологических исследований вы¤вил незначительное увеличение относительного риска (ќ– = 1,24) развити¤ рака молочной железы (–ћ?) у женщин, принимающих на момент исследовани¤ пероральные контрацептивы, преимущественно комбинированные (эстроген + гестаген). Ётот повышенный риск постепенно снижаетс¤ в течение 10 лет после прекращени¤ приема комбинированных пероральных контрацептивов ( ќ ).
ѕоскольку –ћ? редко встречаетс¤ у женщин моложе 40 лет, некоторое увеличение количества подобных диагнозов у женщин, принимающих или недавно принимавших  ќ , невелико по сравнению с общим риском –ћ?. –иск диагностировани¤ –ћ? у женщин, примен¤ющих монопрепараты прогестагена, примерно соответствует таковому при приеме  ќ . ќднако данные по монопрепаратам прогестагена получены в значительно меньших попул¤ци¤х пациенток и ¤вл¤ютс¤ менее убедительными, чем данные по  ќ . ”становить причинно-следственную св¤зь на основе этих исследований не представл¤етс¤ возможным. ¬ы¤вленна¤ картина возрастани¤ риска может обуславливатьс¤ более ранней диагностикой –ћ? у женщин, принимающих пероральные контрацептивы, их биологическим действием или сочетанием этих факторов. ” женщин, принимающих пероральные контрацептивы, вы¤вл¤ютс¤ более ранние клинические стадии –ћ? в сравнении с женщинами, никогда их не принимавших.
¬ редких случа¤х сообщалось о доброкачественных, и еще реже злокачественных опухол¤х печени у пациенток, принимающих диеногест. ¬ отдельных случа¤х эти опухоли приводили к опасным дл¤ жизни внутрибрюшным кровотечени¤м. ?сли у женщины, принимающей препарат, имеют место сильные боли в верхней части живота, увеличена печень или присутствуют признаки внутрибрюшного кровотечени¤, то при дифференциальной диагностике следует учесть веро¤тность наличи¤ опухоли печени.
»зменени¤ минеральной плотности костной ткани (ћѕ )
Ќа фоне приема диеногеста было отмечено снижение ћѕ , поэтому необходимо оценивать ожидаемую пользу его применени¤ по отношению к возможному риску дл¤ каждой пациентки, принима¤ во внимание возможность возникновени¤ факторов риска развити¤ остеопороза, особенно у пациенток с повышенным риском остеопороза, так как во врем¤ лечени¤ диеногестом происходит умеренное снижение концентрации эндогенных эстрогенов. ?енщинам любого возраста важно принимать препарат кальци¤ и витамин D, вне зависимости от соблюдени¤ определенной диеты или применени¤ витаминных добавок.
?ругие состо¤ни¤
Ќеобходимо тщательное наблюдение за пациентками с наличием в анамнезе депрессии. ?сли депресси¤ рецидивирует в серьезной форме, препарат следует отменить.
¬ целом показано, что препарат не вли¤ет на артериальное давление (ј?) у женщин с нормальным ј?. “ем не менее, если на фоне применени¤ диеногеста возникает хроническа¤, клинически значима¤ артериальна¤ гипертензи¤, рекомендуетс¤ отменить препарат и начать гипотензивное лечение.
ѕри рецидиве холестатической желтухи и/или холестатического зуда, которые впервые по¤вились во врем¤ беременности или предшествующего приема половых гормонов, препарат необходимо отменить.
?иеногест может оказывать незначительное вли¤ние на периферическую инсулинорезистентность и толерантность к глюкозе. ѕациентки с сахарным диабетом, особенно при наличии гестационного сахарного диабета в анамнезе, в период терапии диеногестом нуждаютс¤ в тщательном наблюдении.
¬ некоторых случа¤х возможно развитие хлоазмы, особенно у женщин с хлоазмой беременных в анамнезе. ?енщинам со склонностью к хлоазме необходимо избегать воздействи¤ солнечных лучей или ультрафиолетового облучени¤ в период применени¤ препарата.
¬ период терапии препаратом могут возникать персистирующие фолликулы в ¤ичниках (часто называемые функциональными кистами ¤ичников). Ѕольшинство таких фолликулов не имеют клинических про¤влений, хот¤ некоторые могут сопровождатьс¤ болью в области таза.
Ћактоза
¬ одной таблетке препарата «африллаЃ содержитс¤ 62,8 мг лактозы моногидрата. Ќаход¤щимс¤ на безлактозной диете пациенткам с редкими наследственными нарушени¤ми, такими как непереносимость галактозы, дефицит лактазы или глюкозо-галактозна¤ мальабсорбци¤, применение препарата противопоказано.

Influence on the ability to drive vehicles and mechanisms

There was no negative effect of ZafrillaЃ on the ability to drive vehicles and mechanisms, however, patients who have impaired concentration during the adaptation period (the first 3 months of using the drug) should be careful.

Release form

Pills. 2 mg
There are 14 tablets in a PVC - aluminum foil blister.
2 blisters in a cardboard box along with instructions for use.

Storage conditions

In original packaging (blister in a pack) at a temperature not exceeding 30 ? —.
Keep out of the reach of children.

Shelf life

3 years.
Do not use after the expiration date printed on the package.

Vacation conditions

Dispensed by prescription.