SLINDA is a progestin indicated for use by females of reproductive potential to prevent pregnancy.

Posology
How to Use SLINDA
SLINDA is dispensed in a blister card. SLINDA should be started using a Day 1 start.
Table 1 Instructions for Starting or Switching SLINDA

How to Take SLINDA
SLINDA (white active and green inert tablets) is swallowed whole once a day. Take one tablet daily for 28 consecutive days; one white active tablet daily during the first 24 days and one green inert tablet daily during the 4 following days. Tablets must be taken every day at about the same time of the day so that the interval between two tablets is always 24 hours.
Missed Doses
Table 2 Instructions for Missed SLINDA

Advice in Case of Gastrointestinal Disturbances
If vomiting or diarrhea occurs within 3-4 hours after tablet taking, the new tablet (scheduled for the next day) should be taken as soon as possible. The new tablet should be taken within 12 hours of the usual time of tablet-taking if possible. If more than two tablets are missed, the advice concerning missed tablets, including using backup non-hormonal contraception, given above is applicable.
DOSAGE FORMS AND STRENGTHS
SLINDA is supplied in blister cards, each containing 24 round, film-coated, unscored, white tablets and 4 round, film-coated, unscored green tablets.
• Each white tablet contains 4 mg of drospirenone. White tablets are debossed with an “E” on one side and a “D” on the other side
• Each green tablet is inert and does not contain drospirenone. Green tablets are debossed with an “E” on one side and a “4” on the other side.
Paediatric population
Safety and efficacy of Slinda have been established in women of reproductive age. Safety and efficacy are expected to be the same for post pubertal adolescents under the age of 18 and users 18 years and older. Use of this product before menarche is not indicated.
Method of administration
For oral use.

Hyperkalemia
SLINDA contains drospirenone, a progestin, which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk females, comparable to a 25 mg dose of spironolactone. SLINDA is contraindicated in females with conditions that predispose to hyperkalemia (e.g. renal impairment, hepatic impairment, and adrenal insufficiency). Females receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked prior to starting treatment and during the first treatment cycle. Consider monitoring serum potassium concentration in females at increased risk for hyperkalemia i.e., those females who take a strong CYP3A4 inhibitor long-term and concomitantly with SLINDA. Strong CYP3A4 inhibitors include azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g., indinavir, boceprevir), and clarithromycin [see Drug Interactions (7)]. Monitor females taking SLINDA who later develop medical conditions and/or begin medication that put them at an increased risk for hyperkalemia.
Most females with hyperkalemia in the clinical development studies of SLINDA had mild potassium elevations and/or isolated increases that returned to normal while still on study medication. No concurrent adverse reactions were attributed to hyperkalemia. In the pivotal trial, two females (0.2%) with persistent potassium elevations discontinued SLINDA.
Thromboembolic Disorders
Epidemiological studies have not indicated an association between progestin-only preparations and an increased risk of myocardial infarction, cerebral thromboembolism, or venous thromboembolism.
Combined oral contraceptives containing drospirenone and ethinyl estradiol may be associated with a higher risk of venous thromboembolism (VTE) than those containing some other progestins in combination with ethinyl estradiol. It is unknown whether the risk of VTE is increased with drospirenone alone; however, if there is a risk, it is expected to be lower than that of drospirenone in combination with ethinyl estradiol.
When prescribing SLINDA, consider the increased risk of thromboembolism inherent in the postpartum period and in females with a history of thromboembolism
Discontinue SLINDA if arterial or venous thromboembolic events occur. Consider discontinuing SLINDA, if feasible, in case of SLINDA prolonged immobilization due to surgery or illness.
Bone Loss
Treatment with SLINDA leads to decreased estradiol serum levels. It is unknown if this may cause a clinically relevant loss of bone mineral density.
Cervical Cancer
Some studies suggest that use of combination hormonal contraceptives containing progestin and estradiol has been associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

Liver Disease
Discontinue SLINDA if jaundice or acute or chronic disturbances of liver function develop. Do not resume use until markers of liver function return to normal and SLINDA causation has been excluded.
SLINDA is contraindicated in females with liver tumors, benign or malignant, or hepatic impairment [see Use in Specific Populations (8.6)].
Ectopic Pregnancy
Be alert to the possibility of ectopic pregnancy in females who become pregnant or complain of lower abdominal pain while on SLINDA.
Risk of Hyperglycemia in Patients with Diabetes
Some patients receiving progestins, including SLINDA, may exhibit a decrease in insulin sensitivity. Therefore, patients with diabetes may be at greater risk of hyperglycemia and may require additional medication adjustments or monitoring.
Bleeding Irregularities and Amenorrhea
Females using SLINDA may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first three months of use. Bleeding irregularities may resolve over time or by changing to a different contraceptive product. If bleeding persists or occurs after previously regular cycles, evaluate for causes such as pregnancy or malignancy.
Based on subject diaries from four clinical trials of SLINDA, 64.4% of females experienced unscheduled bleeding at Cycle 1. This percentage decreased to 40.3% by cycle 13.
A total of 91 out of 2593 subjects (0.4%) discontinued SLINDA due to menstrual bleeding disorders including metrorrhagia, menstrual irregular, vaginal hemorrhage, menorrhagia, uterine hemorrhage, and amenorrhea.
If scheduled bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or two active tablets or started taking them on a day later than she should have, consider the possibility of pregnancy at the time of the first missed period and perform appropriate diagnostic measures. If the patient has adhered to the prescribed dosing schedule and misses two consecutive periods, rule out pregnancy.
Depression
Carefully observe females for a history of depression and discontinue SLINDA if depression recurs to a serious degree. Data on the association of progestin-only contraceptive products with onset of depression and exacerbation of depression are limited.

DRUG INTERACTIONS
Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.

Effects of Other Drugs on Hormonal Contraceptives
Substances decreasing the systemic concentrations of hormonal contraceptives (HCs) and potentially diminishing the efficacy of HCs:
Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the systemic concentrations of HCs and potentially diminish the effectiveness of HCs or increase breakthrough bleeding.
Some drugs or herbal products that may decrease the effectiveness of HCs include efavirenz, phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, rifabutin, rufinamide, aprepitant, and products containing St. John’s wort.
Interactions between HCs and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel females to use an alternative non-hormonal method of contraception or a back-up method when enzyme inducers are used with HCs, and to continue back-up non-hormonal contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.
Substances increasing the systemic concentrations of hormonal contraceptives (HCs):
In a clinical drug-drug interaction study conducted in premenopausal females, once daily
co-administration of DRSP 3 mg/ethinyl estradiol (EE) 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure.
Influence of SLINDA on other Medicinal Products
Based on in vitro studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrate, an interaction of drospirenone with the metabolism of other active substances is unlikely.
Potential to increase serum potassium concentration:
There is a potential for an increase in serum potassium concentration in females taking SLINDA with other drugs that may increase serum potassium concentration (for example, ACE inhibitors, angiotensin-II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDS [see Warnings and Precautions (5.1)]
 

Pregnancy
Risk Summary
Based on epidemiologic studies and meta-analyses, there is little or no increased risk of birth defects in the children of females who inadvertently use oral progestins during early pregnancy (See Data).

Discontinue SLINDA if pregnancy occurs, because there is no reason to use hormonal contraceptives during pregnancy
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively.
Data
Human Data
Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following maternal use of oral progestins before conception or during early pregnancy.
Lactation
Risk Summary
Negligible amounts of drospirenone are excreted in the breast milk [see Data]. Thus, at therapeutic doses of SLINDA, no effects on breastfed newborns/infants are anticipated. In
general, no adverse effects have been found on milk production or on the health growth, or development of the infant with use of POPs.
Human Data
After daily administration of 4 mg SLINDA tablets, the average DRSP concentration in breast milk over 24-hour period is 5.6 ng/mL. Based on this concentration, the estimated average infant daily dosages for an exclusively breastfed infant is 840 ng/kg/day (relative infant dose is 1.5%).
Pediatric Use
Safety and efficacy of SLINDA have been established in females of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and users 16 years and older.
Study CF111/304 evaluated the bleeding associated with SLINDA in females ≥12 years of age. Bleeding data were generally consistent with those from Study CF111/303 in adult females [see Clinical Studies (14)].
Use of this product before menarche is not indicated.

No studies on the influence on the ability to drive and use machines have been performed with Slinda.
No effects on ability to drive and use machines have been observed in users of oral hormonal contraceptives.

The following clinically significant adverse reactions are described elsewhere in other sections of the labeling:
• Hyperkalemia [see Warnings and Precautions (5.1)]
• Bleeding Irregularities and Amenorrhea [see Warnings and Precautions (5.8)]
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 data described below reflect the exposure of SLINDA in females of reproductive potential desiring to prevent pregnancy based on four clinical studies including Study CF111/303 [see Clinical Studies (14)]. The mean time of SLINDA exposure ranged from 197 to 328 days. The demographic profile for the pooled study data was: mean age 28 years; mean BMI 25 kg/m2; racial distribution was 83% White; 14% Black; 1% Asian and 2% Other.
Table 3 Adverse Reactions Occurring in ≥ 1% of Females Receiving SLINDA in Four Pooled Studies

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 National Pharmacovigilance Centre (NPC):
−Fax: +966-11-205-7662
−Call NPC at +966-11-2038222, Ext 2317-2356-2340
−SFDA Call Center: 19999
−E-mail: npc.drug@sfda.gov.sa
−Website: https://ade.sfda.gov.sa/

There have been no reports of serious deleterious effects from overdosage of SLINDA. Symptoms that may occur include are nausea, vomiting, and vaginal bleeding. There are no antidotes and treatment should be to provide symptomatic support.
Drospirenone is a spironolactone analogue which has antimineralocorticoid properties. Therefore, serum potassium and sodium, and evidence of metabolic acidosis, should be monitored in cases of overdose.

SLINDA (drospirenone) is for use as an oral contraceptive. It is supplied as clear to a slightly opaque PVC-PVDC/Aluminum blister cards, each holding of 24 white tablets each containing 4 mg of drospirenone, a synthetic progestational compound and 4 green inert tablets.
Drospirenone is chemically described as (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)1,3’,4’,6,6a,7,8,9,10,11, 12,13,14,15,15a,16-hexadecahydro10,13-dimethylspiro-[17Hdicyclopropa- [6,7:15,16]cyclopenta[a]phenanthrene-17,2’(5H)-furan]-3,5’(2H)-dione). It has a molecular weight of 366.5, a molecular formula of C24H30O3, and the structural formula below:

Drospirenone is a white to almost white or slightly yellow crystalline powder. It is a progestin and neutral molecule with slight solubility in water
The active tablet is a 5 mm, round, unscored, film-coated, white tablet that contains 4mg of drospirenone as the active ingredient, and microcrystalline cellulose NF, anhydrous lactose NF, colloidal silicon dioxide NF, magnesium stearate NF, polyvinyl alcohol partially hydrolyzed NF, talc NF, titanium dioxide NF, and poly-ethylene glycol NF as the inactive ingredients. Each tablet is debossed with the letter “E” on one side and the letter “D” on the other sides.
The inert tablet is a 5 mm, round, unscored, film-coated, green tablet that does not contain drospirenone. Each inert green tablet contains the following inactive ingredients: Lactose monohydrate NF, corn starch NF, povidone 30000 NF, colloidal silicon dioxide NF, magnesium stearate NF, hypromellose NF, talc NF, titani-um dioxide USP, polysorbate 2910 NF, triacetin NF, FD&C blue 2 aluminum lake and yellow ferric oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
SLINDA progestin-only oral contraceptive lowers the risk of becoming pregnant primarily by suppressing ovulation.
Pharmacodynamics
Drospirenone is a spironolactone analogue with anti-mineralocorticoid activity.
Laboratory Tests
The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, serum levels of (carrier) proteins, e.g., corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis.

Absorption
The pharmacokinetics of oral drospirenone is dose-proportional following single doses ranging from 1-10 mg. Maximum concentrations (Cmax) of drospirenone in plasma of about 27 ng/ml are reached at about 2-6 hours after single ingestion of SLINDA. During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about 41 ng/ml are reached after about 10 days of treatment. Plasma drospirenone Cmax and area under the curve (AUC) accumulate by a factor of about 1.5 to 2 following multiple dose administration of SLINDA. Concomitant ingestion of food has no influence on the extent of absorption of drospirenone.
Distribution

Drospirenone is 95% to 97% bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG). The apparent volume of distribution of drospirenone is approximately 4 L/kg
Elimination
Metabolism
Drospirenone is extensively metabolized after oral administration. The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, formed by reduction and subsequent sulfation. These metabolites were shown not to be pharmacologically active.
Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.
Excretion
DRSP serum concentrations are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces.
Specific Populations
Patients with Hepatic Impairment:
The mean exposure to DRSP in females with moderate liver impairment is approximately three times higher than the exposure in females with normal liver function. SLINDA has not been studied in females with severe hepatic impairment [see Contraindications (4) and Warnings and Precautions (5.5)].
Patients with Renal Impairment:
The effect of renal impairment on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium concentrations were investigated in three separate groups of female subjects (n = 28, age 30–65). All subjects were on a low potassium diet. During the study, 7 subjects continued the use of potassium-sparing drugs for the treatment of their underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP concentrations in the group with CLcr of 50–79 mL/min were comparable to those in the control group with CLcr ≥ 80 mL/min. The serum DRSP concentrations were on average 37% higher in the group with CLcr of 30–49 mL/min compared to those in the control group. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium-sparing drugs during the study, mean serum potassium concentrations increased by up to 0.33 mEq/L. [see Contraindications (4) and Warnings and Precautions (5.1).]
Drug Interaction Studies:
In a clinical drug-drug interaction study conducted in 20 premenopausal females, co- administration of a product containing DRSP (3 mg)/EE (0.02 mg) COC with the strong CYP3A4 inhibitor ketoconazole (200 mg twice daily) for 10 days increased the AUC(0-24h) and Cmax of DRSP by 2.68-fold (90% CI: 2.44, 2.95) and 1.97-fold (90% CI: 1.79, 2.17),
respectively.

NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 24-month oral carcinogenicity study in mice with doses up to 10 mg/kg/day DRSP, equating to 2 times the maximum clinical exposure (based on AUC), there was an increase in carcinomas of the harderian gland in the high dose DRSP group. In a similar study in rats given doses up to 10 mg/kg/day DRSP, 10 times the maximum clinical exposure (based on AUC), there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the high dose DRSP group. Mutagenesis studies for DRSP were conducted in vivo and in vitro and no evidence of mutagenic activity was observed.
CLINICAL STUDIES
Pregnancy Prevention
The efficacy of SLINDA was evaluated in Study CF111/303 (NCT02269241). This single arm multicenter, clinical trial was conducted in the U.S. The efficacy population consisted of 953 females ≤ 35 years of age with 5,547 evaluable cycles. The demographic profile for females was: mean age 26.4 years and mean BMI 28.5 kg/m2. The racial distribution was 53.3% Caucasian; 38.5% African American; 2.2% Asian and 6% other. During these cycles, a total of 17 (1.8%) females reported pregnancy, leading to a Pearl Index (95% CI) of 4.0 (2.3, 6.4).
One female who became pregnant during the study was breastfeeding and not included in the Pearl Index (PI) calculation. The confidence interval for the PI was calculated assuming that events of pregnancy had a Poisson distribution.
Out of the 953 females evaluated for efficacy, 332 subjects had a baseline BMI ≥ 30 (35%) and 173 females had a baseline BMI ≥ 35 (18%). Data were insufficient to analyze PI by BMI subgroups.
Table 4 Pearl Index Based on Evaluable Cycles and Reported Pregnancies in Females
≤ 35 Years of Age in Study CF111/303

Effect on Bleeding Patterns
The bleeding pattern with SLINDA was assessed systematically using patient diaries in Study CF111/303 in adult females.

The percentage of females experiencing scheduled bleeding or unscheduled bleeding/spotting decreased over time. Overall, the percentage of females with scheduled bleeding or spotting decreased from 81% in Cycle 1 to 26% in Cycle 13. Similarly, the overall percentage of females with unscheduled bleeding or spotting decreased from 61% in Cycle 1 to 40% in Cycle 13. The percentages of females with scheduled and unscheduled bleeding or spotting generally decreased through Cycle 10 and were maintained at a consistent level thereafter.
Table 5 Adult Females with Scheduled and Unscheduled Bleeding or Spotting: (Safety Set)

In Study CF111/304 conducted in Europe in post-menarchal, female, adolescents (12 through 17 years of age), bleeding data were generally consistent with those from Study CF111/303 in adult females. SLINDA was associated with a decrease in the percentage of adolescent females experiencing bleeding or spotting over time. The percentage of adolescent females with scheduled bleeding or spotting decreased from 98.0% in Cycle 1 to 28.4% in Cycle 13. The percentage of adolescent females with scheduled bleeding or spotting generally decreased through Cycle 9 and was maintained at a consistent level thereafter. In contrast, the percentage of adolescent females with unscheduled bleeding or spotting was maintained at a relatively consistent level during the study (53.0% in Cycle 1 versus 52.2% in Cycle 13).
In addition to Studies CF111/303 and CF111/304 an additional two studies evaluated bleeding associated with SLINDA. A total of 91 females (0.4%) from these four studies discontinued SLINDA due to problems with irregular bleeding or amenorrhea.

White active film-coated tablets:
Tablet core:
Microcrystalline cellulose
Lactose
Silica, colloidal anhydrous (E551)
Magnesium stearate (E470b)
Tablet coat:
Poly(vinyl alcohol)

Titanium dioxide (E171)
Macrogol
Talc (E553b)
Green placebo film-coated tablets:
Tablet core:
Lactose
Maize starch
Povidone
Silica, colloidal anhydrous (E551)
Magnesium stearate (E470b)
Tablet coat:
Hypromellose (E464)
Triacetin
Polysorbate 80 (E433)
Titanium dioxide (E171)
Indigo carmine aluminium lake (E132)
Yellow Iron Oxide (E172)

Not applicable.

• Store SLINDA below 30°C.
• Keep SLINDA and all medicines out of the reach of children.

SLINDA (drospirenone) tablets is packaged in clear to a slightly opaque PVC-PVDC/Aluminum blister cards. Each blister card holds 24 white round active film-coated tablets, each containing 4mg of drospirenone and 4 green round inert film-coated tablets that do not contain drospirenone. SLINDA is supplied in cardboard cartons containing 1, 3, or 6 blister cards as provided below:
SLINDA 1 blister card (1 x 28 tablets) NDC 0642-7470-01
SLINDA 3 blister cards (3 x 28 tablets) NDC 0642-7470-03
SLINDA 6 blister cards (6 x 28 tablets) NDC 0642-7470-06

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