Latanoprost / Finasteride 0.01/0.1% 30 mL Foam Pump
Latanoprost / Finasteride 0.06/0.1% 30 mL Foam Pump
Latanoprost / Finasteride 0.06/0.2% 30 mL Foam Pump
Latanoprost
Latanoprost, an analog of prostaglandin F2alpha, is a prodrug used to reduce elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Studies have shown that latanoprost administered once daily is at least as effective as timolol in lowering intraocular pressure.12 When latanoprost and timolol were used in combination, a complete or almost complete additive effect in reducing intraocular pressure has been observed.[24740] Treatment has been associated with increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes.[34
Finasteride
Finasteride is a 5-alpha reductase inhibitor used to treat symptomatic benign prostatic hyperplasia (BPH), a condition found in the majority of men over the age of 50. Finasteride has been shown to increase and maintain maximum urine flow rate in men with BPH, although less than 50% of men show improvement despite a reduction in prostate size. In a typical patient undergoing treatment for BPH with finasteride (>= 6 months), a 50% decrease in serum PSA concentrations can be expected; however, individual patients may experience varying decreases in PSA values. During treatment, serum PSA concentrations may decrease even in the presence of prostate cancer. If clinicians use serum PSA concentrations as an aid in the detection of prostate cancer in men receiving finasteride, values should be doubled for comparison with normal ranges in untreated men. Any increase from baseline, even if the value is within the normal range for untreated men, may signal the presence of prostate cancer. If clinicians elect to use percent free PSA (free to total PSA ratio) as a marker, no adjustment in PSA values appear to be necessary as the value is not significantly decreased by finasteride.5 In June 2011, a review of two large, randomized controlled trials, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial prompted the FDA to alert healthcare professionals of the potential risk of an increased incidence of high-grade prostate cancer in patients receiving finasteride or dutasteride treatment. Results from the PCPT trial showed that men receiving finasteride had a 26% decreased risk of being diagnosed with prostate cancer overall when compared to placebo (p < 0.0001); however, the risk reduction was limited to Gleason score (GS) <= 6 cancers. There was an increased incidence of GS 8—10 prostate cancers with finasteride compared to placebo (1.8% vs. 1.1%, respectively).67Finasteride is also used for treating hair loss in men and has been shown to be effective for mild to moderate hair loss of the vertex and anterior mid-scalp area; efficacy in bitemporal recession has not been established. Finasteride (Proscar) was approved by the FDA in June 1992 for the treatment of BPH. Another finasteride oral dosage form, Propecia, was approved by the FDA in December 1997 for the treatment of male pattern baldness (i.e., androgenetic alopecia). Finasteride is also used investigationally as an alternative agent for treating hirsutism.
Latanoprost
Latanoprost is a selective agonist at a subtype of prostaglandin receptors known as the FP receptor. By acting on the FP receptor, latanoprost increases the outflow of aqueous humor thereby reducing intraocular pressure. According to the manufacturer, studies in both animals and man suggest that increased uveoscleral outflow is the primary mechanism of action.[34
Finasteride
Finasteride is a synthetic 4-aza analog of testosterone that acts as a competitive, specific inhibitor of type II 5-alpha-reductase, an intracellular enzyme that converts testosterone to the potent androgen 5-alpha-dihydrotestosterone (DHT). The type II 5alpha-reductase isozyme is primarily found in prostate, seminal vesicles, epididymides, and hair follicles, as well as liver. The type II isozyme is responsible for two-thirds of circulating DHT. DHT is the primary androgen that stimulates the development of prostate tissue. When used for the treatment of benign prostatic hyperplasia, as the enzymatic conversion from testosterone to DHT is inhibited, a desirable reduction in prostate hypertrophy is achieved, and urine flow should be improved. In male pattern hair loss, the balding scalp contains miniaturized hair follicles and increased amounts of DHT compared with hairy scalp. Finasteride decreases scalp and serum DHT concentrations, thus interrupting a key factor in the development of androgenetic alopecia in those patients genetically predisposed. Finasteride does not appear to affect circulating concentrations of cortisol, estradiol, prolactin, thyroid-stimulating hormone, thyroxine or cholesterol. Research to date also suggests that finasteride does not affect the hypothalamic-pituitary-testicular-axis.
Transdermal application results is primarily localized action. As such, the expected pharmacokinetics for each of Arousal Cream’s six compounds mimics those of the individual compounds when administered topically. The differences resulting from simultaneous application have not been studied.
Aminophylline
Theophylline can be administered orally or intravenously. When rapid attainment of therapeutic serum concentrations is desired, IV “loading” doses can be given, although oral administration with regular-release tablets is equally effective. Unbound theophylline serum concentrations are usually in the range of 6—12 mcg/ml and concentrations should be obtained in patients with low protein binding (i.e., neonates, hepatic cirrhosis). Steady state serum concentrations are reached in 30—65 hours in adults. Aminophylline, a salt of theophylline, is the form frequently used for IV therapy. Since 100 mg of aminophylline is equivalent to 80 mg of theophylline, errors in dosing are possible, and clinicians should carefully assess dose adjustments and calculations when switching between aminophylline dose forms and theophylline dose forms.
Protein binding is approximately 40% for healthy adults and is lower in neonates and patients with hepatic impairment. Target peak serum concentration ranges for neonates for the treatment of apnea are therefore lower than those of adults, due to a greater proportion of free “active” theophylline. Unbound theophylline is distributed throughout extracellular body fluids and tissues, however, distribution into body fat is poor. Theophylline readily crosses the placenta and the blood-brain barrier and is excreted into breast milk.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2E1, CYP3A4
Theophylline is primarily metabolized by CYP1A2 isoenzymes, with secondary pathways by CYP2E1 and CYP3A4. In vitro data suggest that while metabolism is mediated by CYP1A2 at low plasma concentrations, metabolism shifts to CYP2E1 at higher concentrations, and metabolism by CYP3A4 is minor, independent of theophylline plasma concentration.32 The manufacturer states that theophylline is a substrate of hepatic enzymes CYP1A2, 2E1, and 3A3 without mention of 3A4 33; however, cytochrome P450 genome experts no longer support the existence of CYP3A3 and instead attribute this isoform to a coding error of or a variant of CYP3A4.3435 Since the therapeutic range is narrow, it is prudent to monitor theophylline serum concentrations upon initiation, dosage adjustment, or discontinuation of medications that may alter the function of CYP1A2, CYP2E1, and/or CYP3A4 isoforms.
In the premature neonate, theophylline is metabolized to caffeine in significant amounts, and this compound can accumulate due to its long half-life. Elimination is usually a first-order process, but zero-order elimination has been reported in some cases. Theophyllines’ half-life varies with patient age, hepatic function, smoking status, and drug interactions. Nonsmoking adults usually have a half-life of 6.5—10.5 hours. Metabolites are eliminated renally, with only about 10% excreted as unchanged theophylline.
Route-Specific Pharmacokinetics:
Oral Route:
Theophylline is generally well absorbed after oral administration. Regular (i.e., nonsustained-release) tablets produce peak serum concentrations within 60 minutes after administration. Liquids and suspensions are absorbed more rapidly. Sustained-release preparations vary in the rate of absorption. Food can delay the rate, but not the extent, of absorption of some sustained-release products. Large volumes of fluid can increase absorption.
Peak concentrations should usually occur 1—2 hours after oral dosing. Serum concentrations of 10—20 mcg/ml (55—110 micromoles/L) generally are regarded as therapeutic, however, the FDA has now lowered the target peak concentration range to 10—15 mcg/ml to minimize the risk of adverse reactions. Most clinicians use 8—15 mcg/ml as the target range.
Elderly
Absorption of pentoxifylline from the gastrointestinal tract following oral administration is rapid and almost complete. There is significant first-pass effect after absorption. Peak plasma levels are attained within 2—4 hours. The rate but not the extent of absorption is affected by coadministration with food.
Special Populations
Renal Impairment
Ergoloid Mesylate
Ergoloid mesylates (dihydroergocornine, dihydroergocristine, and dihydroergocryptine) are administered orally. Ergoloid mesylates undergo significant (about 50%) first-pass hepatic metabolism. The mean half-life of ergoloid mesylates is about 3.5 hours (range 2.6 to 5.1 hours).24
Affected Cytochrome P450 enzymes and drug transporters: None known.
Route-Specific Pharmacokinetics
Oral Route
Ergoloid mesylates are rapidly absorbed from the gastrointestinal tract, but oral bioavailability is approximately 25%. Peak plasma concentrations occur within 1.5 to 3 hours. The finding of lower peak levels of ergoloid compared to the total drug-metabolite composite is consistent with a considerable first-pass liver metabolism, with less than 50% of the therapeutic moiety reaching the systemic circulation after oral administration. Oral tablet or solution dosage forms and sublingual dosage forms result in similar bioavailability. The clinical therapeutic effects of a particular dose may not be apparent for 3 to 4 weeks.24
Special Populations
Hepatic Impairment Ergoloid mesylates are extensively metabolized in the liver.24
Renal Impairment No data are available but renal impairment is not expected to have a significant effect on ergoloid mesylate pharmacokinetics.
Indications/Dosage
For the symptomatic management of Alzheimer’s disease, vascular dementia, or primary progressive dementia
Oral dosage
Adults 1 mg PO 3 times per day. Clinical improvement may take 3 to 4 weeks after initiating therapy. Assess treatment benefits periodically. It is not known if there are patient traits that would usefully predict a positive response to ergoloid mesylates therapy. While doses up to 9 mg/day (3 mg PO 3 times per day) have been studied, statistically significant differences in effect at higher doses than the labeled dose have not been noted. The role of ergoloid mesylates in the management of dementia remains controversial. The majority of studies evaluating ergoloid mesylates for vascular dementia were conducted prior to the development of standardized diagnostic criteria and study results have been inconsistent. Practice guidelines do not support the use of ergoloid mesylates in the treatment of Alzheimer’s disease.241336141516
Maximum Dosage Limits
Adults 3 mg/day PO is usual dose; doses up to 9 mg/day have been studied.
Geriatric 3 mg/day PO is usual dose; doses up to 9 mg/day have been studied.
Adolescents Safety and efficacy have not been established.
Children Safety and efficacy have not been established.
Infants Not indicated.
Patients with Hepatic Impairment Dosing No guidelines for dosage adjustment are available; use with caution in patients with hepatic disease as ergoloid mesylates are extensively metabolized in the liver.24
Patients with Renal Impairment Dosing No dosage adjustment is needed.
Pentoxifylline
Pentoxifylline is administered orally. The distribution of pentoxifylline has not been fully characterized, but it is known that the drug and its metabolites are distributed into breast milk (see Contraindications/Precautions).
Metabolism of pentoxifylline occurs in both the erythrocytes and the liver. All metabolites contribute to the hematological effects of pentoxifylline. The 5-hydroxyhexyl metabolite is equivalent to pentoxifylline in its pharmacologic effects. Once absorbed, pentoxifylline is metabolized rapidly by the erythrocytes to its 5-hydroxyhexyl metabolite and by the liver to its 3-carboxypropyl metabolite. The plasma half-lives of pentoxifylline and its metabolites are 0.4—0.8 hours and 1.6—1.8 hours, respectively. The elimination half-lives of pentoxifylline and its 5-hydroxyhexyl metabolite increase with increasing doses of the drug, but the elimination half-life of the 3-carboxypropyl metabolite does not. Excretion of pentoxifylline and its metabolites is primarily renal. The manufacturer states that the drug does not accumulate in plasma with multiple oral doses in patients with normal renal function.
Route-Specific Pharmacokinetics
Oral Route
Limited data indicate that the pentoxifylline AUC is increased and elimination rate decreased in patients aged 60—80 years when compared to younger adults (22—30 years). In elderly patients, dosage adjustments may be necessary based on tolerability and/or decreased renal function (see Dosage).
In patients with renal impairment (i.e., CrCl < 50 ml/min), the 5-hydroxyhexyl metabolite of pentoxifylline accumulates; eight hours after dose administration, the peak plasma concentration is reduced by 78% in patients with normal renal function, by 45% in patients with a CrCl of 10—20 ml/min, and by 11% in patients with a CrCl of < 10 ml/min. Dosage adjustments are recommended in patients with a CrCl of < 50 ml/min (see Dosage).3738 In elderly patients, dosage adjustments may be necessary based on tolerability and/or decreased renal function (see Dosage).
Special Populations:
Hepatic Impairment:
Cirrhosis can prolong the half-life of theophylline to as long as 24 hours.
Pediatrics:
In children age 1—9 years, the half-life of theophylline can be as short as 4—5 hours. Neonates (<3 months old) have a much higher rate of excretion of unchanged theophylline (approximately 50%).
Smoking:
In smokers, the half-life of theophylline can be as short as 4—5 hours.
Cor pulmonale:
Cor pulmonale can prolong the half-life of theophylline to as long as 24 hours.
Pulmonary edema:
pulmonary edema can prolong the half-life of theophylline to as long as 24 hours.
Sildenafil
As earlier stated, sildenafil citrate can be administered orally, sublingually, or intravenously. In the management of erectile dysfunction, however, the oral and sublingual routes are the means by which the medication is commonly administered. After oral ingestion, sildenafil citrate is rapidly absorbed within the small intestine, with a peak plasma concentration time of anywhere between 30 and 120 minutes and a median time of 60 minutes in fasting individuals. It has a bioavailability of approximately 40 percent after oral administration.248
Metabolism of sildenafil citrate occurs primarily in the liver through the action of the hepatic microsomal isoenzymes cytochrome P450 3A4 and 2C9. After the action of the isoenzymes on sildenafil, it is broken down into an N-desmethyl metabolite. Both sildenafil citrate as well as its N-desmethyl metabolite breakdown product are tightly bound to plasma proteins and they have an approximate half-life of four hours. it is estimated that about 96 percent of sildenafil and its metabolite are bound to plasma proteins after oral ingestion. Following its metabolism, the majority of sildenafil citrate is excreted in the stool; a lesser amount, about 13 percent of sildenafil metabolites, is excreted in the urine.48
There are a number of factors that can interfere with the metabolism of sildenafil, thereby increasing or decreasing its concentration in the body. Some of these factors include the following:
Hepatic impairment: Individuals who have significant hepatic disease such as liver cirrhosis may experience a significant increase in plasma sildenafil levels. This is because the production of the hepatic isoenzymes cytochrome P450 3A4 and 2C9 are markedly diminished in liver cirrhosis. As a result of this diminished production of the hepatic isoenzymes, the body is not able to adequately metabolize sildenafil citrate, resulting in increased plasma levels.
Renal impairment: Individuals with significant renal disease as evidenced with a creatinine clearance of less than 30mL/min will have a marked increase in plasma sildenafil levels after oral ingestion. Since sildenafil and its metabolites are excreted through the kidneys, renal diseases will impair the ability of the kidneys to perform this task adequately.
Age: For reasons that are yet to be fully determined, there is a 40 percent increase in the plasma levels of sildenafil and its N-desmethyl metabolite when administered to men greater than 65 years of age.
Cytochrome P450 3A4 inhibitors: The concomitant use of drugs known to inhibit the hepatic cytochrome P450 enzymes may result in increased plasma levels of sildenafil. Examples of drugs that are known P450 inhibitors are macrolide antibiotics such as erythromycin, antifungal agents such as ketoconazole, and protease inhibitors such as indinavir. By inhibiting the production of cytochrome P450, hepatic metabolism of sildenafil does not occur, leading to its increased levels in plasma.8
Arginine
Arginine is administered orally and via IV administration. Thirty grams of intravenous arginine increased urinary nitrate and cyclic GMP excretion rates by 97 +/- 28 and 66 +/- 20%, respectively. The onset and duration of vasodilator effect on endogenous nitric oxide production paralleled the plasma half-life of arginine.30
Route-Specific Pharmacokinetics:
Intravenous Route: Arginine elimination was biphasic, with concentration dependent renal clearance eliciting a rapid initial decrease in serum concentrations, followed by a slower decrease in serum concentrations due to nonrenal elimination.31 After 30 g IV infusion, about 5 g of arginine was excreted in the urine, with a major portion excreted within 90 minutes after drug administration. Renal clearance in 2 of 12 volunteers within the first 90 minutes after drug administration was 1.16—1.18 mL/kg/minute.31 In a study of 8 healthy males, after receiving 30 g IV of arginine, clearance was 544 +/- 24 mL/min, and after 6 g IV of arginine, clearance was 894 +/-164 mL/min. Elimination half life was dose dependent and was 41.6 min after 30 g IV and 59.6 min after 6 g IV.30
Testosterone
Testosterone is administered intramuscularly (IM); via subcutaneous injection; to the skin as a topical gel, solution, ointment or transdermal systems for transdermal absorption; by implantation of long-acting pellets, or; via buccal systems.
In serum, testosterone is bound to protein. It has a high affinity for sex hormone binding globulin (SHBG) and a low affinity for albumin. The albumin-bound portion freely dissociates. The affinity for SHBG changes throughout life. It is high during prepuberty, declines during adolescence and adult life, then rises again in old age. The active metabolite DHT has a greater affinity for SHBG than testosterone. Elimination half-life is 10—100 minutes and is dependent on the amount of free testosterone in the plasma.
Testosterone is metabolized primarily in the liver to various 17-keto steroids. It is a substrate for hepatic cytochrome P450 (CYP) 3A4 isoenzyme.39 Estradiol and dihydrotestosterone (DHT) are the major active metabolites, and DHT undergoes further metabolism. Testosterone activity appears to depend on formation of DHT, which binds to cytosol receptor proteins. Further metabolism of DHT takes place in reproductive tissues. About 90% of an intramuscular testosterone dose is excreted in the urine as conjugates of glucuronic and sulfuric acids. About 6% is excreted in the feces, largely unconjugated. There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes.40
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp
Testosterone is a substrate for CYP3A4 and is also both transported by and an inhibitor of P-glycoprotein (P-gp) transport.3941
Route-Specific Pharmacokinetics
Nasal Route: For intranasal use only; do not administer to other parts of the body. For first time use of the nasal gel, prime the pump by rotating the actuator over a sink and discarding any dispensed product. Wipe the tip of the dispenser clean with a dry tissue. Before administration, blow your nose and ensure the dispenser cap is removed from the dispenser pen. Slowly advance the tip of the actuator into the left nostril upwards until the finger on the pump reaches the base of the nose. Tilt the actuator so that the opening on the tip of the actuator is in contact with the lateral wall of the nostril to ensure that the gel is applied to the nasal wall. Slowly rotate the bottom of the dispenser pen to administer an actuation. Each actuation (click) of the metered dose pump dispenses 5 mg of testosterone. Remove the actuator from the nose while wiping the tip along the inside of the lateral nostril wall to fully transfer the gel. Repeat steps for administration of the next actuation, this time to the lateral wall of the right nostril. Wipe the tip of the actuator with a dry tissue, replace dispenser cap. Press on the nostrils at a point just below the bridge of the nose and lightly massage. Do not blow the nose or sniff for 1 hour after administration of the intranasal gel. If any gel gets on the hands, it is recommended to wash hands with warm water and soap.
Latanoprost
Latanoprost should not be used in patients with closed-angle glaucoma, or inflammatory or neovascular glaucoma. There is limited experience with latanoprost in these patients.
Latanoprost should be used with caution in patients with aphakia, pseudophakic patients with a torn posterior lens capsule, and patients with known risk factors for macular edema. Macular edema, including cystoid macular edema, has been reported during treatment with this drug.[34
Recipients of latanoprost may experience a gradual increase in pigmentation (i.e., brown coloration) of the iris and periorbital tissue (eyelids), which may not be noticeable for several months to years. Patients who develop increased pigmentation may continue to receive treatment; however, these patients should be examined regularly as they may develop photophobia or be more sensitive to sunlight (UV) exposure. After discontinuing latanoprost, the change in iris color is likely to be permanent, while the pigmentation change in the periorbital tissue may be reversible in some patients. Eyelash changes (i.e., increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of eyelashes) has also been associated with the use of latanoprost. Eyelash changes are usually reversible upon treatment discontinuation. Inform drug recipients of the possibility of iridal and eyelid discoloration, and of the potential for eyelash changes.[34
Latanoprost should be used with caution in patients with active intraocular inflammation (e.g., iritis, uveitis). Use of latanoprost in these patient may exacerbate inflammation.[3 4
Instruct drug recipients to remove contact lenses before instilling latanoprost ophthalmic drops. Lenses may be reinserted 15 minutes after drug administration. The ophthalmic solution is formulated with the preservative benzalkonium chloride, which may be absorbed by soft contact lenses.[34
The use of multiple dose containers of ophthalmic products has been associated with bacterial keratitis. Inadvertent contamination of the latanoprost containers may increase the risk of infection in ocular surgery patients, or in patients who develop an ocular infection or ocular trauma, including corneal abrasion. If there is any damage to the ocular epithelial surface, latanoprost should be used with caution. Reactivation of herpes simplex keratitis has been reported during latanoprost therapy. Use caution in patients with a history of herpetic keratitis; avoid use in patients with active herpes simplex keratitis due to the potential for exacerbation of inflammation.[3
Latanoprost is classified as FDA pregnancy risk category C. Although there are no adequate and well-controlled studies in pregnant women, limited experience in human pregnancy has not resulted in clinically significant risk to the fetus. A minimal amount of drug reaches systemic circulation after ophthalmic administration, suggesting exposure of the drug to the fetus is low.11 According to the manufacturer, latanoprost should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[3
According to the manufacturer, it is not known whether latanoprost or its metabolites are excreted in breast milk. Because systemic plasma concentrations of latanoprost are low and the half-life is short after ophthalmic administration, clinically significant amounts of the drug would not be expected to be excreted in breast-milk.11 To further minimize the amount of drug that reaches the systemic circulation and breast milk, apply pressure over the tear duct by the corner of the eye for 1 minute after ophthalmic administration. According to the manufacturer, caution should be exercised when latanoprost is administered during breast-feeding.[3 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Safety and efficacy of latanoprost have not been established in the pediatric population (i.e., neonates, infants, children, or adolescents).[34
Latanoprost should be used cautiously in patients with renal disease (e.g., renal failure, renal impairment) or hepatic disease. There have been no studies on safe use in these patients.
Finasteride
Finasteride is not indicated for use in adolescents, children, or infants. Safety and effectiveness have not been established in pediatric patients under 18 years of age.510
Finasteride should be used with caution in patients with hepatic disease, since finasteride is metabolized extensively in the liver. Data are lacking regarding the incidence of adverse effects or drug accumulation in patients with hepatic impairment.
Finasteride reduces total serum prostate specific antigen (PSA). In a typical patient undergoing treatment for BPH with finasteride (>= 6 months), a 50% decrease in serum PSA concentrations can be expected; however, individual patients may experience varying decreases in PSA values. During treatment, serum PSA concentrations may decrease even in the presence of prostate cancer. If clinicians use serum PSA concentrations as an aid in the detection of prostate cancer in men receiving finasteride, values should be doubled for comparison with normal ranges in untreated men. Any increase from baseline, even if the value is within the normal range for untreated men, may signal the presence of prostate cancer. If clinicians elect to use percent free PSA (free to total PSA ratio) as a marker, no adjustment in PSA values appear to be necessary as the value is not significantly decreased by finasteride.5 In June 2011, a review of two large, randomized controlled trials, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial prompted the FDA to alert healthcare professionals of the potential risk of an increased incidence of high-grade prostate cancer in patients receiving finasteride or dutasteride treatment. Results from the PCPT trial showed that men receiving finasteride had a 26% decreased risk of being diagnosed with prostate cancer when compared to placebo (p < 0.0001); however, the risk reduction was limited to Gleason score (GS) <= 6 cancers. There was an increased incidence of GS 8—10 prostate cancers with finasteride compared to placebo (1.8% vs. 1.1%, respectively).67Therefore, in initiating or continuing treatment with finasteride, clinicians should weigh the known benefits of treatment against the potential risk and be aware that finasteride may increase the risk of high-grade prostate cancer. Further, lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out other urological diseases prior to treatment with finasteride. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5-alpha-reductase inhibitor therapy and should be carefully monitored for urinary tract obstruction.5
Men treated with finasteride should refrain from blood donation while taking finasteride. The purpose of this is to prevent administration of finasteride to a pregnant female transfusion recipient.
Clinical efficacy studies of finasteride for hair loss did not include subjects aged 65 and over. Based on the pharmacokinetics of finasteride 5 mg, no dosage adjustment is necessary in the geriatric patient. However, the efficacy of finasteride for hair loss in the elderly has not been established.
The clinical significance of finasteride’s effect on semen characteristics for an individual male patient’s fertility is not known; consider the potential effects on semen when assessing a male with infertility. Finasteride may cause spermatogenesis inhibition or oligospermia, decreased sperm motility, or decreased semen volume. In a 52-week, randomized, double-blind, placebo-controlled study in healthy men, finasteride (5 mg PO once daily) significantly decreased total sperm count (-34.3%) compared to baseline at 26 weeks but not at 52 weeks or at the 24-week follow-up. Semen volume was decreased at 52 weeks for finasteride (-14.5%), but the effect was not statistically significant. Sperm concentration was decreased by finasteride (-7.4%) but was not significant for either drug. Significant reductions of 6 to 12% in sperm motility were observed during treatment. Sperm morphology was not affected. One subject taking finasteride had decreases in sperm count of more than 90% of baseline values at 52 weeks; partial recovery was noted at the 24-week follow-up. During post marketing surveillance, male infertility and/or poor seminal quality following treatment discontinuation have been reported. It should be noted that normalization or improvement of seminal quality has also been reported after discontinuation of finasteride.
Latanoprost
Latanoprost is classified as FDA pregnancy risk category C. Although there are no adequate and well-controlled studies in pregnant women, limited experience in human pregnancy has not resulted in clinically significant risk to the fetus. A minimal amount of drug reaches systemic circulation after ophthalmic administration, suggesting exposure of the drug to the fetus is low.11 According to the manufacturer, latanoprost should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[3
Finasteride
Finasteride is not FDA-approved for use in females of childbearing potential and is contraindicated during pregnancy. Finasteride may cause fetal harm. Finasteride and other 5-alpha-reductase inhibitors, by inhibiting the conversion of testosterone to DHT, have the ability to cause abnormalities in the external genitalia of the male fetus. Pregnant women or females trying to conceive should not handle crushed or broken finasteride tablets. The distribution of finasteride into human semen has been assessed and appears to be well below the threshold concentration associated with fetal anomalies in animals.
Latanoprost
According to the manufacturer, it is not known whether latanoprost or its metabolites are excreted in breast milk. Because systemic plasma concentrations of latanoprost are low and the half-life is short after ophthalmic administration, clinically significant amounts of the drug would not be expected to be excreted in breast-milk.11 To further minimize the amount of drug that reaches the systemic circulation and breast milk, apply pressure over the tear duct by the corner of the eye for 1 minute after ophthalmic administration. According to the manufacturer, caution should be exercised when latanoprost is administered during breast-feeding.[3 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Finasteride
Finasteride is not FDA-approved for use in females of childbearing potential and is recommended to be avoided during breast-feeding. It is not known whether finasteride is excreted in human milk. Therefore, the effects of finasteride on breast-feeding or a nursing infant cannot be determined.
Latanoprost
Asthma or asthma exacerbations (bronchospasm) and dyspnea have been reported during postmarketing experience with latanoprost.[3
Infection (i.e., upper respiratory tract infection, naso-pharyngitis, influenza) was reported in 3% of patients receiving latanoprost during clinical trials. Cases of herpes keratitis have been reported with postmarketing use.[3
Postmarketing use of latanoprost has been associated with cases of palpitations, unstable angina, and chest pain (unspecified).[3
Myalgia, arthralgia, musculoskeletal pain, and back pain were reported in 1% of patients during latanoprost clinical trials.[3
Rash and other allergic skin reactions were reported at a rate of 1% during latanoprost clinical trials. Cases of pruritus and toxic epidermal necrolysis have been reported during postmarketing use of latanoprost.[3
Dizziness and headache have been reported during postmarketing experience with latanoprost.[3
Finasteride
Adverse reactions to finasteride are generally mild and transient. In a long-term (4 years) clinical trial in men with benign prostatic hypertrophy (BPH) [25064], the most frequently reported adverse reactions to finasteride were related to sexual function. At 1 year, the adverse reactions reported to be drug-related were impotence (erectile dysfunction), decreased libido, decreased ejaculate volume, ejaculation dysfunction, breast enlargement, breast tenderness (mastalgia), and rash (unspecified). There was no significant difference between finasteride and placebo in the incidences of impotence, decreased libido, and ejaculation dysfunction in years 2 to 4 of the study. However, during post marketing surveillance, continued erectile dysfunction, orgasm dysfunction or other orgasm disorders, and ejaculation dysfunction following treatment discontinuation have been reported.510 From June 1992, when finasteride was approved, until February 1995, the FDA received reports of gynecomastia in 214 men (median age: 71 yrs). Most were taking a dose of 5 mg/day PO. Gynecomastia has been the most frequently reported adverse effect of this drug since it was marketed. The onset of gynecomastia ranged from 14 days to 2.5 years (median: 180 days). Thirty percent had unilateral gynecomastia, 25% had bilateral involvement, and, in the remainder of reports, this information was not specified. Twenty-seven percent of patients were also taking other medications that are known to cause gynecomastia. Gynecomastia resolved either completely or partially in 80% of subjects after finasteride was discontinued, however, in at least 2 cases, a new primary malignancy of primary intraductal breast cancer subsequently developed.13 In a 4 to 6 year trial where patients were randomized to receive finasteride 5 mg/day, doxazosin 4 or 8 mg/day, a combination of the two drugs, or placebo, four patients reported breast cancer as an adverse experience; three of the patients were receiving finasteride therapy and one patient was receiving combination therapy. In addition, male breast cancer has been reported during post-marketing experience. Other post-marketing adverse reactions have included depression, testicular pain that continued after discontinuation of treatment, and hypersensitivity reactions including pruritus, urticaria, and angioedema (including swelling of the lips, tongue, throat, and face).5
In controlled trials of finasteride for the treatment of male pattern hair loss, 1.4% of patients discontinued therapy due to adverse events, compared with 1.6% of placebo-treated patients. Discontinuation of therapy because of a drug-related sexual adverse experience occurred in 1.2% of patients on finasteride and 0.9% of patients on placebo. The following adverse events were reported as at least possibly drug-related in finasteride-treated patients: libido decrease (1.8%), impotence (1.3%), and ejaculation disorder (1.2%), primarily decreased ejaculate volume. The incidence of each of the above adverse effects decreased to <= 0.3% by the fifth year of treatment. During post marketing surveillance, decreased libido and libido disorders that continued after discontinuation of treatment was reported.5
Finasteride may cause spermatogenesis inhibition or oligospermia, decreased sperm motility, or decreased semen volume. The clinical significance of finasteride’s effect on semen characteristics for an individual male patient’s fertility is not known; consider the potential effects on semen when assessing a male with infertility. In a 52-week, randomized, double-blind, placebo-controlled study in healthy men, finasteride (5 mg PO once daily) significantly decreased total sperm count (-34.3%) compared to baseline at 26 weeks but not at 52 weeks or at the 24-week follow-up. Semen volume was decreased at 52 weeks for finasteride (-14.5%), but the effect was not statistically significant. Sperm concentration was decreased by finasteride (-7.4%) but was not significant for either drug. Significant reductions of 6 to 12% in sperm motility were observed during treatment. Sperm morphology was not affected. One subject taking finasteride had decreases in sperm count of more than 90% of baseline values at 52 weeks; partial recovery was noted at the 24-week follow-up. During post marketing surveillance, male infertility and/or poor seminal quality following treatment discontinuation have been reported. It should be noted that normalization or improvement of seminal quality has also been reported after discontinuation of finasteride.51012
By inhibiting the conversion of testosterone to DHT, finasteride and other 5-alpha-reductase inhibitors have the ability to cause teratogenesis, specifically abnormalities in the external genitalia of the male fetus (e.g., hypospadias).
Store this medication in a refrigerator between 36°F to 46°F (2°C – 8°C). Do not freeze. Protect from light. Keep all medicine out of the reach of children. Throw away any medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.
