Famotidine Oral Suspension

Dosage Form: powder, for oral suspension
FAMOTIDINE FOR ORAL SUSPENSION

Famotidine Oral Suspension Description

The active ingredient famotidine, is a histamine H2-receptor antagonist. Famotidine is N'-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide. The empirical formula of famotidine is C8H15N7O2S3 and its molecular weight is 337.43. Its structural formula is:

Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol.

Each 5 mL of the oral suspension when prepared as directed contains 40 mg of famotidine and the following inactive ingredients: citric acid, flavors, microcrystalline cellulose and carboxymethylcellulose sodium, sucrose and xanthan gum. Added as preservatives are sodium benzoate 0.1%, sodium methylparaben 0.1%, and sodium propylparaben 0.02%.

CLINICAL PHARMACOLOGY IN ADULTS

GI Effects

Famotidine is a competitive inhibitor of histamine H2-receptors. The primary clinically important pharmacologic activity of famotidine is inhibition of gastric secretion. Both the acid concentration and volume of gastric secretion are suppressed by famotidine, while changes in pepsin secretion are proportional to volume output.

In normal volunteers and hypersecretors, famotidine inhibited basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After oral administration, the onset of the antisecretory effect occurred within one hour; the maximum effect was dose-dependent, occurring within one to three hours. Duration of inhibition of secretion by doses of 20 and 40 mg was 10 to 12 hours.

Single evening oral doses of 20 and 40 mg inhibited basal and nocturnal acid secretion in all subjects; mean nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours. The same doses given in the morning suppressed food-stimulated acid secretion in all subjects. The mean suppression was 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively, 8 to 10 hours after administration. In some subjects who received the 20-mg dose, however, the antisecretory effect was dissipated within 6-8 hours. There was no cumulative effect with repeated doses. The nocturnal intragastric pH was raised by evening doses of 20 and 40 mg of famotidine to mean values of 5.0 and 6.4, respectively. When famotidine was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 or 40 mg of famotidine was raised to about 5.

Famotidine had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and exocrine pancreatic function were not affected by famotidine.

Other Effects

Systemic effects of famotidine in the CNS, cardiovascular, respiratory or endocrine systems were not noted in clinical pharmacology studies. Also, no antiandrogenic effects were noted. (See ADVERSE REACTIONS.) Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with famotidine.

Pharmacokinetics

Famotidine for oral suspension is incompletely absorbed. The bioavailability of oral doses is 40-45%. Famotidine tablets and famotidine for oral suspension are bioequivalent. Bioavailability may be slightly increased by food, or slightly decreased by antacids; however, these effects are of no clinical consequence. Famotidine undergoes minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1-3 hours. Plasma levels after multiple doses are similar to those after single doses. Fifteen to 20% of famotidine in plasma is protein bound. Famotidine has an elimination half-life of 2.5-3.5 hours. Famotidine is eliminated by renal (65-70%) and metabolic (30-35%) routes. Renal clearance is 250-450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65-70% of an intravenous dose are recovered in the urine as unchanged compound. The only metabolite identified in man is the S-oxide.

There is a close relationship between creatinine clearance values and the elimination half-life of famotidine. In patients with severe renal insufficiency, i.e., creatinine clearance less than 10 mL/min, the elimination half-life of famotidine may exceed 20 hours and adjustment of dose or dosing intervals in moderate and severe renal insufficiency may be necessary (see PRECAUTIONS, DOSAGE AND ADMINISTRATION).

In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of famotidine. However, in elderly patients with decreased renal function, the clearance of the drug may be decreased (see PRECAUTIONS, Geriatric Use).

Clinical Studies

Duodenal Ulcer

In a U.S. multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer, orally administered famotidine was compared to placebo. As shown in Table 1, 70% of patients treated with famotidine 40 mg h.s. were healed by week 4.

Table 1 Outpatients with Endoscopically Confirmed Healed Duodenal Ulcers

	Famotidine 40 mg h.s. (N=89)	Famotidine 20 mg b.i.d. (N=84)	Placebo h.s. (N=97)
* Statistically significantly different than placebo (p<0.001)
Week 2	*32%	*38%	17%
Week 4	*70%	*67%	31%

Patients not healed by week 4 were continued in the study. By week 8, 83% of patients treated with famotidine had healed versus 45% of patients treated with placebo. The incidence of ulcer healing with famotidine was significantly higher than with placebo at each time point based on proportion of endoscopically confirmed healed ulcers.

In this study, time to relief of daytime and nocturnal pain was significantly shorter for patients receiving famotidine than for patients receiving placebo; patients receiving famotidine also took less antacid than the patients receiving placebo.

Long-Term Maintenance

Treatment of Duodenal Ulcers

Famotidine, 20 mg p.o. h.s., was compared to placebo h.s. as maintenance therapy in two double-blind, multicenter studies of patients with endoscopically confirmed healed duodenal ulcers. In the U.S. study the observed ulcer incidence within 12 months in patients treated with placebo was 2.4 times greater than in the patients treated with famotidine. The 89 patients treated with famotidine had a cumulative observed ulcer incidence of 23.4% compared to an observed ulcer incidence of 56.6% in the 89 patients receiving placebo (p<0.01). These results were confirmed in an international study where the cumulative observed ulcer incidence within 12 months in the 307 patients treated with famotidine was 35.7%, compared to an incidence of 75.5% in the 325 patients treated with placebo (p<0.01).

Gastric Ulcer

In both a U.S. and an international multicenter, double-blind study in patients with endoscopically confirmed active benign gastric ulcer, orally administered famotidine, 40 mg h.s., was compared to placebo h.s. Antacids were permitted during the studies, but consumption was not significantly different between the famotidine and placebo groups. As shown in Table 2, the incidence of ulcer healing (dropouts counted as unhealed) with famotidine was statistically significantly better than placebo at weeks 6 and 8 in the U.S. study, and at weeks 4, 6 and 8 in the international study, based on the number of ulcers that healed, confirmed by endoscopy.

Table 2 Patients with Endoscopically Confirmed Healed Gastric Ulcers

	U.S. Study		International Study
	Famotidine 40 mg h.s. (N=74)	Placebo h.s. (N=75)	Famotidine 40 mg h.s. (N=149)	Placebo h.s. (N=145)
***,†Statistically significantly better than placebo (p≤0.05, p≤0.01 respectively)
Week 4	45%	39%	†47%	31%
Week 6	†66%	44%	†65%	46%
Week 8	***78%	64%	†80%	54%

Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients receiving famotidine than for patients receiving placebo; however, in neither study was there a statistically significant difference in the proportion of patients whose pain was relieved by the end of the study (week 8).

Gastroesophageal Reflux Disease (GERD)

Orally administered famotidine was compared to placebo in a U.S. study that enrolled patients with symptoms of GERD and without endoscopic evidence of erosion or ulceration of the esophagus. Famotidine 20 mg b.i.d. was statistically significantly superior to 40 mg h.s. and to placebo in providing a successful symptomatic outcome, defined as moderate or excellent improvement of symptoms (Table 3).

Table 3 % Successful Symptomatic Outcome

	Famotidine 20 mg b.i.d. (N=154)	Famotidine 40 mg h.s. (N=149)	Placebo (N=73)
* p≤0.01 vs Placebo
Week 6	82*	69	62

By two weeks of treatment symptomatic success was observed in a greater percentage of patients taking famotidine for 20 mg b.i.d. compared to placebo (p≤0.01).

Symptomatic improvement and healing of endoscopically verified erosion and ulceration were studied in two additional trials. Healing was defined as complete resolution of all erosions or ulcerations visible with endoscopy. The U.S. study comparing famotidine 40 mg p.o. b.i.d. to placebo and famotidine 20 mg p.o. b.i.d. showed a significantly greater percentage of healing for Famotidine 40 mg b.i.d. at weeks 6 and 12 (Table 4).

Table 4 % Endoscopic Healing - U.S. Study

	Famotidine 40 mg b.i.d. (N=127)	Famotidine 20 mg b.i.d. (N=125)	Placebo (N=66)
* p≤0.01 vs Placebo † p≤0.01 vs Famotidine 20 mg b.i.d. ‡ p≤0.05 vs Famotidine 20 mg b.i.d.
Week 6	48*,†	32	18
Week 12	69*,‡	54*	29

As compared to placebo, patients who received famotidine had faster relief of daytime and nighttime heartburn and a greater percentage of patients experienced complete relief of nighttime heartburn. These differences were statistically significant.

In the international study, when famotidine 40 mg p.o. b.i.d. was compared to ranitidine 150 mg p.o. b.i.d., a statistically significantly greater percentage of healing was observed with famotidine for 40 mg b.i.d. at week 12 (Table 5). There was, however, no significant difference among treatments in symptom relief.

Table 5 % Endoscopic Healing - International Study

	Famotidine 40 mg b.i.d. (N=175)	Famotidine 20 mg b.i.d. (N=93)	Ranitidine 150 mg b.i.d. (N=172)
* p≤0.05 vs Ranitidine 150 mg b.i.d.
Week 6	48	52	42
Week 12	71*	68	60

Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)

In studies of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome with or without multiple endocrine adenomas, famotidine significantly inhibited gastric acid secretion and controlled associated symptoms. Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion below 10 mEq/hr; initial doses were titrated to the individual patient need and subsequent adjustments were necessary with time in some patients. Famotidine was well tolerated at these high dose levels for prolonged periods (greater than 12 months) in eight patients, and there were no cases reported of gynecomastia, increased prolactin levels, or impotence which were considered to be due to the drug.

CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS

Pharmacokinetics

Table 6 presents pharmacokinetic data from clinical trials and a published study in pediatric patients (<1 year of age; N=27) given famotidine I.V. 0.5 mg/kg and from published studies of small numbers of pediatric patients (1-15 years of age) given famotidine intravenously. Areas under the curve (AUCs) are normalized to a dose of 0.5 mg/kg I.V. for pediatric patients 1-15 years of age and compared with an extrapolated 40 mg intravenous dose in adults (extrapolation based on results obtained with a 20 mg I.V. adult dose).

Table 6 Pharmacokinetic Parameters* of Intravenous Famotidine

Age (N=number of patients)	Area Under the Curve (AUC) (ng-hr/mL)	Total Clearance (Cl) (L/hr/kg)	Volume of Distribution (Vd) (L/kg)	Elimination Half-life (T1/2) (hours)
* Values are presented as means ± SD unless indicated otherwise. † Single center study. ‡ Multicenter study. § Mean value only.
0-1 month† (N=10)	NA	0.13 ± 0.06	1.4 ± 0.4	10.5 ± 5.4
0-3 months‡ (N=6)	2688 ± 847	0.21 ± 0.06	1.8 ± 0.3	8.1 ± 3.5
>3–12 months‡ (N=11)	1160 ± 474	0.49 ± 0.17	2.3 ± 0.7	4.5 ± 1.1
1-11 yrs (N=20)	1089 ± 834	0.54 ± 0.34	2.07 ± 1.49	3.38 ± 2.60
11-15 yrs (N=6)	1140 ± 320	0.48 ± 0.14	1.5 ± 0.4	2.3 ± 0.4
Adult (N=16)	1726§	0.39 ± 0.14	1.3 ± 0.2	2.83 ± 0.99

Plasma clearance is reduced and elimination half-life is prolonged in pediatric patients 0-3 months of age compared to older pediatric patients. The pharmacokinetic parameters for pediatric patients, ages >3 months-15 years, are comparable to those obtained for adults.

Bioavailability studies of 8 pediatric patients (11-15 years of age) showed a mean oral bioavailability of 0.5 compared to adult values of 0.42 to 0.49. Oral doses of 0.5 mg/kg achieved AUCs of 645 ± 249 ng-hr/mL and 580 ± 60 ng-hr/mL in pediatric patients <1 year of age (N=5) and in pediatric patients 11-15 years of age, respectively, compared to 482 ± 181 ng-hr/mL in adults treated with 40 mg orally.

Pharmacodynamics

Pharmacodynamics of famotidine were evaluated in 5 pediatric patients 2-13 years of age using the sigmoid Emax model. These data suggest that the relationship between serum concentration of famotidine and gastric acid suppression is similar to that observed in one study of adults (Table 7).

Table 7 Pharmacodynamics of famotidine using the sigmoid Emax model

	EC50 (ng/mL)*
* Serum concentration of famotidine associated with 50% maximum gastric acid reduction. Values are presented as means ± SD.
Pediatric Patients	26 ± 13
Data from one study
a) healthy adult subjects	26.5 ± 10.3
b) adult patients with upper GI bleeding	18.7 ± 10.8

Five published studies (Table 8) examined the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients. While each study had a different design, acid suppression data over time are summarized as follows:

Table 8

Dosage	Route	Effect*	Number of Patients (age range)
* Values reported in published literature. † Mean (95% confidence interval). ‡ Means ± SD.
0.5 mg/kg, single dose	I.V.	gastric pH >4 for 19.5 hours (17.3, 21.8)†	11 (5-19 days)
0.3 mg/kg, single dose	I.V.	gastric pH >3.5 for 8.7 ± 4.7‡ hours	6 (2-7 years)
0.4-0.8 mg/kg	I.V.	gastric pH >4 for 6-9 hours	18 (2-69 months)
0.5 mg/kg, single dose	I.V.	a >2 pH unit increase above baseline in gastric pH for >8 hours	9 (2-13 years)
0.5 mg/kg b.i.d.	I.V.	gastric pH >5 for 13.5 ± 1.8‡ hours	4 (6-15 years)
0.5 mg/kg b.i.d.	oral	gastric pH >5 for 5.0 ± 1.1‡ hours	4 (11-15 years)

The duration of effect of famotidine I.V. 0.5 mg/kg on gastric pH and acid suppression was shown in one study to be longer in pediatric patients <1 month of age than in older pediatric patients. This longer duration of gastric acid suppression is consistent with the decreased clearance in pediatric patients <3 months of age (see Table 6).

Indications and Usage for Famotidine Oral Suspension

Famotidine is indicated in:

1. Short-term treatment of active duodenal ulcer. Most adult patients heal within 4 weeks; there is rarely reason to use famotidine at full dosage for longer than 6 to 8 weeks. Studies have not assessed the safety of famotidine in uncomplicated active duodenal ulcer for periods of more than eight weeks.


2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer. Controlled studies in adults have not extended beyond one year.


3. Short-term treatment of active benign gastric ulcer. Most adult patients heal within 6 weeks. Studies have not assessed the safety or efficacy of famotidine in uncomplicated active benign gastric ulcer for periods of more than 8 weeks.


4. Short-term treatment of gastroesophageal reflux disease (GERD). Famotidine is indicated for short-term treatment of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
   
   
   Famotidine is also indicated for the short-term treatment of esophagitis due to GERD including erosive or ulcerative disease diagnosed by endoscopy (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).


5. Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).

Contraindications

Hypersensitivity to any component of these products. Cross sensitivity in this class of compounds has been observed. Therefore, famotidine should not be administered to patients with a history of hypersensitivity to other H2-receptor antagonists.

Precautions

General

Symptomatic response to therapy with famotidine does not preclude the presence of gastric malignancy.

Patients with Moderate or Severe Renal Insufficiency

Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, longer intervals between doses or lower doses may need to be used in patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency to adjust for the longer elimination half-life of famotidine (see CLINICAL PHARMACOLOGY IN ADULTS and DOSAGE AND ADMINISTRATION).

Information for Patients

The patient should be instructed to shake the oral suspension vigorously for 5-10 seconds prior to each use. Unused constituted oral suspension should be discarded after 30 days.

Drug Interactions

No drug interactions have been identified. Studies with famotidine in man, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man include warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic drug extraction has been tested and no significant effects have been found.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 106 week study in rats and a 92-week study in mice given oral doses of up to 2000 mg/kg/day (approximately 2500 times the recommended human dose for active duodenal ulcer), there was no evidence of carcinogenic potential for famotidine.

Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed.

In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day, fertility and reproductive performance were not affected.

Pregnancy

Pregnancy Category B

Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day, respectively, and in both species at I.V. doses of up to 200 mg/kg/day, and have revealed no significant evidence of impaired fertility or harm to the fetus due to famotidine. While no direct fetotoxic effects have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral doses of 200 mg/kg/day (250 times the usual human dose) or higher. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Studies performed in lactating rats have shown that famotidine is secreted into breast milk. Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose. Famotidine is detectable in human milk. Because of the potential for serious adverse reactions in nursing infants from famotidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Patients <1 year of age

Use of famotidine in pediatric patients <1 year of age is supported by evidence from adequate and well-controlled studies of famotidine in adults, and by the following studies in pediatric patients <1 year of age.

Two pharmacokinetic studies in pediatric patients <1 year of age (N=48) demonstrated that clearance of famotidine in patients >3 months to 1 year of age is similar to that seen in older pediatric patients (1-15 years of age) and adults. In contrast, pediatric patients 0-3 months of age had famotidine clearance values that were 2- to 4-fold less than those in older pediatric patients and adults. These studies also show that the mean bioavailability in pediatric patients <1 year of age after oral dosing is similar to older pediatric patients and adults. Pharmacodynamic data in pediatric patients 0-3 months of age suggest that the duration of acid suppression is longer compared with older pediatric patients, consistent with the longer famotidine half-life in pediatric patients 0-3 months of age. (See CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS, Pharmacokinetics and Pharmacodynamics.)

In a double-blind, randomized, treatment-withdrawal study, 35 pediatric patients <1 year of age who were diagnosed as having gastroesophageal reflux disease were treated for up to 4 weeks with Famotidine Oral Suspension (0.5 mg/kg/dose or 1 mg/kg/dose). Although an intravenous famotidine formulation was available, no patients were treated with intravenous famotidine in this study. Also, caregivers were instructed to provide conservative treatment including thickened feedings. Enrolled patients were diagnosed primarily by history of vomiting (spitting up) and irritability (fussiness). The famotidine dosing regimen was once daily for patients <3 months of age and twice daily for patients ≥3 months of age. After 4 weeks of treatment, patients were randomly withdrawn from the treatment and followed an additional 4 weeks for adverse events and symptomatology. Patients were evaluated for vomiting (spitting up), irritability (fussiness) and global assessments of improvement. The study patients ranged in age at entry from 1.3 to 10.5 months (mean 5.6 ± 2.9 months), 57% were female, 91% were white and 6% were black. Most patients (27/35) continued into the treatment-withdrawal phase of the study. Two patients discontinued famotidine due to adverse events. Most patients improved during the initial treatment phase of the study. Results of the treatment-withdrawal phase were difficult to interpret because of small numbers of patients. Of the 35 patients enrolled in the study, agitation was observed in 5 patients on famotidine that resolved when the medication was discontinued; agitation was not observed in patients on placebo (see ADVERSE REACTIONS, Pediatric Patients).

These studies suggest that a starting dose of 0.5 mg/kg/dose of Famotidine Oral Suspension may be of benefit for the treatment of GERD for up to 4 weeks once daily in patients <3 months of age and twice daily in patients 3 months to <1 year of age; the safety and benefit of famotidine treatment beyond 4 weeks have not been established. Famotidine should be considered for the treatment of GERD only if conservative measures (e.g., thickened feedings) are used concurrently and if the potential benefit outweighs the risk.

Pediatric Patients 1-16 years of age

Use of famotidine in pediatric patients 1-16 years of age is supported by evidence from adequate and well-controlled studies of famotidine in adults, and by the following studies in pediatric patients: In published studies in small numbers of pediatric patients 1-15 years of age, clearance of famotidine was similar to that seen in adults. In pediatric patients 11-15 years of age, oral doses of 0.5 mg/kg were associated with a mean area under the curve (AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1-15 years of age, intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated intravenously with 40 mg. Limited published studies also suggest that the relationship between serum concentration and acid suppression is similar in pediatric patients 1-15 years of age as compared with adults. These studies suggest a starting dose for pediatric patients 1-16 years of age as follows:

Peptic ulcer - 0.5 mg/kg/day p.o. at bedtime or divided b.i.d. up to 40 mg/day.

Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations - 1.0 mg/kg/day p.o. divided b.i.d. up to 40 mg b.i.d.

While published uncontrolled studies suggest effectiveness of famotidine in the treatment of gastroesophageal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or pH determination (gastric or esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric patients have employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day for GERD with or without esophagitis including erosions and ulcerations.

Geriatric Use

Of the 4,966 subjects in clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 and older, and 88 subjects (1.7%) were greater than 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. However, greater sensitivity of some older individuals cannot be ruled out.

No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS, Pharmacokinetics). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Dosage adjustment in the case of moderate or severe renal impairment is necessary (see PRECAUTIONS, Patients with Moderate or Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency).

Adverse Reactions

The adverse reactions listed below have been reported during domestic and international clinical trials in approximately 2500 patients. In those controlled clinical trials in which famotidine tablets were compared to placebo, the incidence of adverse experiences in the group which received famotidine tablets, 40 mg at bedtime, was similar to that in the placebo group.

The following adverse reactions have been reported to occur in more than 1% of patients on therapy with famotidine in controlled clinical trials, and may be causally related to the drug: headache (4.7%), dizziness (1.3%), constipation (1.2%) and diarrhea (1.7%).

The following other adverse reactions have been reported infrequently in clinical trials or since the drug was marketed. The relationship to therapy with famotidine has been unclear in many cases. Within each category the adverse reactions are listed in order of decreasing severity:

Body as a Whole: fever, asthenia, fatigue

Cardiovascular: arrhythmia, AV block, palpitation

Gastrointestinal: cholestatic jaundice, liver enzyme abnormalities, vomiting, nausea, abdominal discomfort, anorexia, dry mouth

Hematologic: rare cases of agranulocytosis, pancytopenia, leukopenia, thrombocytopenia

Hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjunctival injection

Musculoskeletal: musculoskeletal pain including muscle cramps, arthralgia

Nervous System/Psychiatric: grand mal seizure; psychic disturbances, which were reversible in cases for which follow-up was obtained, including hallucinations, confusion, agitation, depression, anxiety, decreased libido; paresthesia; insomnia; somnolence. Convulsions, in patients with impaired renal function, have been reported very rarely.

Respiratory: bronchospasm, interstitial pneumonia

Skin: toxic epidermal necrolysis/Stevens Johnson syndrome (very rare), alopecia, acne, pruritus, dry skin, flushing

Special Senses: tinnitus, taste disorder

Other: rare cases of impotence and rare cases of gynecomastia have been reported; however, in controlled clinical trials, the incidences were not greater than those seen with placebo.

The adverse reactions reported for famotidine tablets may also occur with famotidine for oral suspension.

Pediatric Patients

In a clinical study in 35 pediatric patients <1 year of age with GERD symptoms [e.g., vomiting (spitting up), irritability (fussing)], agitation was observed in 5 patients on famotidine that resolved when the medication was discontinued.

Overdosage

The adverse reactions in overdose cases are similar to the adverse reactions encountered in normal clinical experience (see ADVERSE REACTIONS). Oral doses of up to 640 mg/day have been given to adult patients with pathological hypersecretory conditions with no serious adverse effects. In the event of overdosage, treatment should be symptomatic and supportive. Unabsorbed material should be removed from the gastrointestinal tract, the patient should be monitored, and supportive therapy should be employed.

The oral LD50 of famotidine in male and female rats and mice was greater than 3000 mg/kg and the minimum lethal acute oral dose in dogs exceeded 2000 mg/kg. Famotidine did not produce overt effects at high oral doses in mice, rats, cats and dogs, but induced significant anorexia and growth depression in rabbits starting with 200 mg/kg/day orally. The intravenous LD50 of famotidine for mice and rats ranged from 254-563 mg/kg and the minimum lethal single I.V. dose in dogs was approximately 300 mg/kg. Signs of acute intoxication in I.V. treated dogs were emesis, restlessness, pallor of mucous membranes or redness of mouth and ears, hypotension, tachycardia and collapse.

Famotidine Oral Suspension Dosage and Administration

Duodenal Ulcer

Acute Therapy:

The recommended adult oral dosage for active duodenal ulcer is 40 mg once a day at bedtime. Most patients heal within 4 weeks; there is rarely reason to use famotidine at full dosage for longer than 6 to 8 weeks. A regimen of 20 mg b.i.d. is also effective.

Maintenance Therapy:

The recommended adult oral dose is 20 mg once a day at bedtime.

Benign Gastric Ulcer

Acute Therapy:

The recommended adult oral dosage for active benign gastric ulcer is 40 mg once a day at bedtime.

Gastroesophageal Reflux Disease (GERD)

The recommended oral dosage for treatment of adult patients with symptoms of GERD is 20 mg b.i.d. for up to 6 weeks. The recommended oral dosage for the treatment of adult patients with esophagitis including erosions and ulcerations and accompanying symptoms due to GERD is 20 or 40 mg b.i.d. for up to 12 weeks (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).

Dosage for Pediatric Patients <1 year of age Gastroesophageal Reflux Disease (GERD)

See PRECAUTIONS, Pediatric Patients <1 year of age.

The studies described in PRECAUTIONS, Pediatric Patients <1 year of age suggest the following starting doses in pediatric patients <1 year of age: Gastroesophageal Reflux Disease (GERD) - 0.5 mg/kg/dose of Famotidine Oral Suspension for the treatment of GERD for up to 8 weeks once daily in patients <3 months of age and 0.5 mg/kg/dose twice daily in patients 3 months to <1 year of age. Patients should also be receiving conservative measures (e.g., thickened feedings). The use of intravenous famotidine in pediatric patients <1 year of age with GERD has not been adequately studied.

Dosage for Pediatric Patients 1-16 years of age

See PRECAUTIONS, Pediatric Patients 1-16 years of age.

The studies described in PRECAUTIONS, Pediatric Patients 1-16 years of age suggest the following starting doses in pediatric patients 1-16 years of age:

Peptic ulcer - 0.5 mg/kg/day p.o. at bedtime or divided b.i.d. up to 40 mg/day.

Gastroesophageal Reflux Disease with or without esophagitis including erosions and ulcerations - 1.0 mg/kg/day p.o. divided b.i.d. up to 40 mg b.i.d.

While published uncontrolled studies suggest effectiveness of famotidine in the treatment of gastroesophageal reflux disease and peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or pH determination (gastric or esophageal) and endoscopy. Published uncontrolled clinical studies in pediatric patients 1-16 years of age have employed doses up to 1 mg/kg/day for peptic ulcer and 2 mg/kg/day for GERD with or without esophagitis including erosions and ulcerations.

Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)

The dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose for pathological hypersecretory conditions is 20 mg q 6 h. In some patients, a higher starting dose may be required. Doses should be adjusted to individual patient needs and should continue as long as clinically indicated. Doses up to 160 mg q 6 h have been administered to some adult patients with severe Zollinger-Ellison Syndrome.

Oral Suspension

Famotidine for oral suspension may be substituted for famotidine tablets in any of the above indications. Each five mL contains 40 mg of famotidine after constitution of the powder with 46 mL of Purified Water as directed.

Directions for Preparing Famotidine for Oral Suspension

Prepare suspension at time of dispensing. Slowly add 46 mL of Purified Water. Shake vigorously for 5-10 seconds immediately after adding the water and immediately before use.

Stability of Famotidine for Oral Suspension

Unused constituted oral suspension should be discarded after 30 days.

Concomitant Use of Antacids

Antacids may be given concomitantly if needed.

Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency

In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency, the elimination half-life of famotidine is increased. For patients with severe renal insufficiency, it may exceed 20 hours, reaching approximately 24 hours in anuric patients. Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of famotidine may be reduced to half the dose or the dosing interval may be prolonged to 36-48 hours as indicated by the patient's clinical response.

Based on the comparison of pharmacokinetic parameters for famotidine in adults and pediatric patients, dosage adjustment in pediatric patients with moderate or severe renal insufficiency should be considered.

How is Famotidine Oral Suspension Supplied

Famotidine for oral suspension is a white to off-white powder containing 400 mg of famotidine for constitution. When constituted as directed, famotidine for oral suspension is a smooth, mobile, off-white, homogeneous suspension with a cherry-banana-mint flavor, containing 40 mg of famotidine

Tekamlo

Pronunciation: a-lis-KYE-ren/am-LOE-di-peen
Generic Name: Aliskiren/Amlodipine
Brand Name: Tekamlo

Tekamlo may cause birth defects, or fetal or newborn death if you take it while you are pregnant. If you think you may be pregnant, contact your doctor right away.

Tekamlo is used for:

Treating high blood pressure. It may be used alone or with other medicines. It may also be used for other conditions as determined by your doctor.

Tekamlo is a renin inhibitor and calcium channel blocker combination. It works by relaxing the blood vessels.

Do NOT use Tekamlo if:

• you are allergic to any ingredient in Tekamlo


• you have a history of angioedema (swelling of the hands, face, lips, eyes, throat, or tongue; difficulty swallowing or breathing; or hoarseness) caused by treatment with Tekamlo


• you are pregnant


• you are taking cyclosporine or itraconazole

Contact your doctor or health care provider right away if any of these apply to you.

Before using Tekamlo:

Some medical conditions may interact with Tekamlo. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances (including other blood pressure medicines)


• if you are a woman of childbearing age


• you have a history of angioedema (swelling of the hands, face, lips, eyes, throat, or tongue; difficulty swallowing or breathing; or hoarseness), especially when taking an angiotensin-converting enzyme (ACE) inhibitor (eg, lisinopril)


• if you are dehydrated, have low blood volume, have high blood potassium levels or low blood sodium levels, or are on a low-salt (sodium) diet


• if you have a history of gout, gallbladder or liver problems, kidney problems (eg, renal artery stenosis), low blood pressure, blood vessel problems, or heart problems (eg, heart failure, angina, narrowing of heart blood vessels)


• if you have diabetes, especially if you are also taking an ACE inhibitor (eg, lisinopril) or an angiotensin receptor blocker (eg, losartan)


• if you are on dialysis or will be having surgery


• if you are taking another medicine for blood pressure or heart problems

Some MEDICINES MAY INTERACT with Tekamlo. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Diuretics (eg, furosemide, hydrochlorothiazide) or sildenafil because the risk of low blood pressure may be increased


• ACE inhibitors (eg, lisinopril, angiotensin receptor blockers (eg, losartan), potassium-sparing diuretics (eg, triamterene), or potassium supplements because the risk of high blood potassium levels may be increased


• Atorvastatin, azole antifungals (eg, itraconazole, ketoconazole), conivaptan, cyclosporine, or HIV protease inhibitors (eg, ritonavir) because they may increase the risk of Tekamlo's side effects, including low blood pressure


• Simvastatin because the risk of it's side effects may be increased by Tekamlo

This may not be a complete list of all interactions that may occur. Ask your health care provider if Tekamlo may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Tekamlo:

Use Tekamlo as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Tekamlo. Talk to your pharmacist if you have questions about this information.


• Take Tekamlo by mouth with or without food. It is important to take it consistently with regard to meals. If you take it with food, try to always take it with food. If you prefer to take it on an empty stomach, then try to always take it on an empty stomach.


• Be sure to drink enough liquids while you are taking Tekamlo. If you do not, you may become dehydrated, which may increase your risk of low blood pressure. Discuss any questions or concerns with your doctor.


• Take Tekamlo on a regular schedule to get the most benefit from it. Taking Tekamlo at the same time each day will help you remember to take it.


• Continue to take Tekamlo even if you feel well. Do not miss any doses.


• If you miss a dose of Tekamlo, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Tekamlo.

Important safety information:

• Tekamlo may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Tekamlo with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Tekamlo may cause dizziness, lightheadedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects.


• It may take up to 4 weeks to get the full benefit from Tekamlo. Do not stop using Tekamlo without checking with your doctor.


• Tekamlo may cause a serious side effect called angioedema. Contact your doctor at once if you develop swelling of the hands, face, lips, eyes, throat, or tongue; difficulty swallowing or breathing; or hoarseness.


• Patients who take medicine for high blood pressure often feel tired or run down for a few weeks after starting treatment. Be sure to take your medicine even if you may not feel "normal." Tell your doctor if you develop any new symptoms.


• Check with your doctor before you use a salt substitute or a product that has potassium in it.


• High-fat meals may decrease the amount of Tekamlo that is absorbed into your body. Be sure you take Tekamlo consistently with regard to meals. Discuss any questions or concerns with your doctor.


• If vomiting, diarrhea, or excessive sweating occur, you will need to take care not to become dehydrated. This could increase your risk of low blood pressure. Contact your doctor for instructions.


• Tell your doctor or dentist that you take Tekamlo before you receive any medical or dental care, emergency care, or surgery.


• Talk with your doctor or pharmacist about all of your blood pressure medicines and how to use them. Do not start, stop, or change the dose of any blood pressure medicine unless your doctor tells you to.


• Lab tests, including blood pressure, kidney function, and blood electrolyte levels, may be performed while you use Tekamlo. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Tekamlo with caution in the ELDERLY; they may be more sensitive to its effects.


• Tekamlo should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Tekamlo may cause birth defects, or fetal or newborn death if you take it while you are pregnant. If you think you may be pregnant, contact your doctor right away. It is not known if Tekamlo is found in breast milk. Do not breast-feed while taking Tekamlo.

Possible side effects of Tekamlo:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; dizziness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing or swallowing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue; unusual hoarseness); change in the amount of urine produced; chest pain (new or worsening); fainting; fast or irregular heartbeat; muscle pain or weakness; numbness of an arm or leg; severe or persistent dizziness or lightheadedness; shortness of breath; sudden, severe headache or vomiting; sudden, unexplained weight gain; sudden vision changes; swelling of the feet, ankles, or hands; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Tekamlo side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include fainting; fast or slow heartbeat; severe dizziness or lightheadedness.

Proper storage of Tekamlo:

Store Tekamlo at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Tekamlo out of the reach of children and away from pets.

General information:

• If you have any questions about Tekamlo, please talk with your doctor, pharmacist, or other health care provider.


• Tekamlo is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Tekamlo. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Tekamlo resources

• Tekamlo Side Effects (in more detail)
• Tekamlo Use in Pregnancy & Breastfeeding
• Tekamlo Drug Interactions
• Tekamlo Support Group
• 0 Reviews for Tekamlo - Add your own review/rating

• Tekamlo Prescribing Information (FDA)


• Tekamlo Advanced Consumer (Micromedex) - Includes Dosage Information


• Tekamlo Consumer Overview

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• High Blood Pressure

Nifedipine

Pronunciation: nye-FED-i-peen
Generic Name: Nifedipine
Brand Name: Procardia

Nifedipine is used for:

Treating certain kinds of angina (chest pain). It may also be used for other conditions as determined by your doctor.

Nifedipine is a calcium channel blocking agent. It works to decrease chest pain by dilating (widening) blood vessels in the heart and other blood vessels.

Do NOT use Nifedipine if:

• you are allergic to any ingredient in Nifedipine


• you have very low blood pressure or shock due to heart problems


• you have had a heart attack within the past 2 weeks


• you are taking a barbiturate (eg, phenobarbital), carbamazepine, a hydantoin (eg, phenytoin), a rifamycin (eg, rifampin, rifabutin), or St. John's wort

Contact your doctor or health care provider right away if any of these apply to you.

Before using Nifedipine:

Some medical conditions may interact with Nifedipine. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of angina, heart blood vessel problems, or other heart problems (eg, aortic stenosis; congestive heart failure; heart attack; fast, slow, or irregular heartbeat); high or low blood pressure; liver problems (eg, cirrhosis); kidney problems; swelling of the arms or legs; or fluid in your lungs


• if you take medicines to lower your blood pressure


• if you have recently had or will be having surgery, or if you have recently stopped taking a beta-blocker (eg, propranolol)

Some MEDICINES MAY INTERACT with Nifedipine. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Alpha-blockers (eg, doxazosin), beta-blockers (eg, propranolol), diuretics (eg, hydrochlorothiazide, furosemide), methyldopa, or phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil, tadalafil) because the risk of low blood pressure may be increased


• Acarbose because high blood sugar may occur


• Azole antifungals (eg, ketoconazole, fluconazole), calcium channel blockers (eg, diltiazem, verapamil), cimetidine, fluoxetine, HIV protease inhibitors (eg, ritonavir, saquinavir), imatinib, macrolide antibiotics (eg, erythromycin, clarithromycin), nefazodone, streptogramins (eg, quinupristin/dalfopristin), or valproic acid because they may increase the risk of Nifedipine's side effects


• Barbiturates (eg, phenobarbital), carbamazepine, hydantoins (eg, phenytoin), rifamycins (eg, rifampin, rifabutin), or St. John's wort because they may decrease Nifedipine's effectiveness


• Cyclosporine, digoxin, ketanserin, lithium, tacrolimus, theophylline, or vinca alkaloids (eg, vincristine) because the risk of their side effects may be increased by Nifedipine


• Quinidine, theophylline, or vinca alkaloids (eg, vincristine) because their effectiveness may be decreased by Nifedipine

This may not be a complete list of all interactions that may occur. Ask your health care provider if Nifedipine may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Nifedipine:

Use Nifedipine as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Nifedipine by mouth with or without food.


• Do not eat grapefruit or drink grapefruit juice while you use Nifedipine.


• Swallow Nifedipine whole. Do not break, crush, or chew before swallowing.


• Do not suddenly stop taking Nifedipine without checking with your doctor. If you need to stop Nifedipine, your doctor may gradually lower your dose.


• If you miss a dose of Nifedipine, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Nifedipine.

Important safety information:

• Nifedipine may cause dizziness or light-headedness. These effects may be worse if you take it with alcohol or certain medicines. Use Nifedipine with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Nifedipine may cause dizziness, light-headedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, stit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects.


• Do NOT take more than the recommended dose without checking with your doctor.


• Proper dental care is important while you are taking Nifedipine. Brush and floss your teeth and visit the dentist regularly.


• Tell your doctor or dentist that you take Nifedipine before you receive any medical or dental care, emergency care, or surgery.


• If your doctor has instructed you to check your blood pressure regularly, be sure to do so.


• Use Nifedipine with caution in the ELDERLY; they may be more sensitive to its effects.


• Nifedipine should not be used in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Nifedipine while you are pregnant. Nifedipine is found in breast milk. Do not breast-feed while taking Nifedipine.

Possible side effects of Nifedipine:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; cough; dizziness; flushing; giddiness; headache; heat sensation; heartburn; light-headedness; muscle cramps; nausea; nervousness; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); fainting; fever, chills, or persistent sore throat; mental or mood changes; red, swollen, blistered, or peeling skin; severe or persistent dizziness or light-headedness; shortness of breath; slow, fast, or irregular heartbeat; sudden, unusual weight gain; swelling of the arms or legs; symptoms of heart attack (eg, chest, jaw, or left arm pain; numbness in an arm or leg; sudden, severe headache or vomiting); tender, bleeding, or swollen gums; tremors; unusual bruising or bleeding; unusual tiredness or weakness; vision problems; wheezing; worsening chest pain (eg, longer, more often, more severe); yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Nifedipine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include fainting; loss of consciousness; rapid, slow, or irregular heartbeat; severe dizziness or light-headedness.

Proper storage of Nifedipine:

Store Nifedipine at room temperature, between 59 and 77 degrees F (15 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Nifedipine out of the reach of children and away from pets.

General information:

• If you have any questions about Nifedipine, please talk with your doctor, pharmacist, or other health care provider.


• Nifedipine is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Nifedipine. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Nifedipine resources

• Nifedipine Side Effects (in more detail)
• Nifedipine Dosage
• Nifedipine Use in Pregnancy & Breastfeeding
• Drug Images
• Nifedipine Drug Interactions
• Nifedipine Support Group
• 20 Reviews for Nifedipine - Add your own review/rating

• Nifedipine Professional Patient Advice (Wolters Kluwer)


• Nifedipine Monograph (AHFS DI)


• Adalat Consumer Overview


• Adalat CC Prescribing Information (FDA)


• Afeditab CR Prescribing Information (FDA)


• Nifediac CC Prescribing Information (FDA)


• Nifedical XL Prescribing Information (FDA)


• Procardia Prescribing Information (FDA)


• Procardia XL Prescribing Information (FDA)


• nifedipine Advanced Consumer (Micromedex) - Includes Dosage Information

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• Angina Pectoris Prophylaxis
• Heart Failure
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• Hypertensive Emergency
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• Migraine Prevention
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Urea Emulsion

Urea Emulsion 50% 

(50% Urea) In a zinc undecylenate and lactic acid vehicle

For external use only. Not for ophthalmic use. Do not use on eyes, lips or mucous membranes.

DESCRIPTION: Urea Emulsion 50% contains a keratolytic solution, which is gentle, yet potent, tissue softener for nails and dry rough skin. Urea Emulsion 50% contains 50% urea along with acrylates copolymer, carbomer, cetyl alcohol, disodium EDTA, dl-alphatocopheryl acetate, glycerin, lactic acid, linoleic acid, mineral oil, PEG-6, polysorbate 60, purified water, sodium hydroxide solution, stearic acid, titanium dioxide, zinc undecylenate.

Urea is a diamide of carbonic acid with the following chemical structure:

CLINICAL PHARMACOLOGY: Urea gently dissolves the intercellular matrix, which results in loosening the horny layer of skin while shedding scaly skin at regular intervals, which then softens the hyperkeratotic areas. Urea also hydrates and gently dissolves the intercellular matrix of the nail plate, which can result in the softening and eventual debridement of the nail plate.

PHARMACOKINETICS: The mechanism of action of topically applied urea is not yet known.

INDICATIONS AND USES: For debridement and promotion of normal healing of hyperkeratotic surface lesions, particularly where healing is retarded by local infection, necrotic tissue, fibrinous or purulent debris or eschar. Urea is useful for the treatment of hyper-keratotic conditions such as dry, rough skin, dermatitis, psoriasis, ichthyosis, keratoderma, eczema, keratosis pilaris, keratosis palmaris, xerosis, corns and calluses, as well as damaged, devitalized, and ingrown nails.

CONTRAINDICATIONS: Known hypersensitivity to any of the listed ingredients.

WARNINGS: For external use only. Avoid contact with eyes, lips or mucous membranes.

PRECAUTIONS: This medication is to be used as directed by a physician and should not be used to treat any condition other than that for which it was prescribed. If redness or irritation occurs, discontinue use.

PREGNANCY: Pregnancy Category B. Animal reproduction studies have revealed no evidence of harm to the fetus; however, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Urea Emulsion 50% should be given to a pregnant woman only if clearly needed.

NURSING MOTHERS: It is not known whether or not this drug is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when Urea Emulsion 50% is administered to a nursing women.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

ADVERSE REACTIONS: Transient stinging, burning, itching or irritation may occur and normally disappear upon discontinuing the medication.

Call your doctor for medical advice about side effects.

DOSAGE AND ADMINISTRATION: Apply Urea Emulsion 50% to diseased or damaged nail and/or skin tissue twice per day, or as directed by a physician. (Apply to moistened skin for best results.)

HOW SUPPLIED:

Urea Emulsion 50% NDC # 42808-0206-10 is supplied in a 10 oz (283.5 g) tube.

STORAGE: Store at controlled room temperature 15 to 30°C (59 to 86°F).

Protect from freezing.

Manufactured in the U.S.A. for Exact-Rx, Inc., Melville, NY 11747

00-0206-10-205-00

Iss:5/11

PRINCIPAL DISPLAY PANEL

For External Use Only

NDC 42808-0206-10        Rx Only

Urea

In a zinc undecylenate &

lactic acid vehicle

50%

EMULSION

Exact-Rx.

INCORPORATED

Net Wt. 10 oz (284 g)

UREA  urea  emulsion

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 42808-206 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength UREA (UREA) UREA 500 mg  in 1 g

Inactive Ingredients Ingredient Name Strength CARBOMER COPOLYMER TYPE A   CARBOMER HOMOPOLYMER TYPE C   CETYL ALCOHOL   EDETATE DISODIUM   .ALPHA.-TOCOPHEROL ACETATE, DL-   GLYCERIN   LACTIC ACID   LINOLEIC ACID   MINERAL OIL   PEG-6 STEARATE   POLYSORBATE 60   WATER   SODIUM HYDROXIDE   STEARIC ACID   TITANIUM DIOXIDE   ZINC UNDECYLENATE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 42808-206-10 1 TUBE In 1 CARTON contains a TUBE 1 284 g In 1 TUBE This package is contained within the CARTON (42808-206-10)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
UNAPPROVED DRUG OTHER		08/01/2011

Labeler - Exact-Rx, Inc. (137953498)

Revised: 08/2011Exact-Rx, Inc.

More Urea Emulsion resources

• Urea Emulsion Use in Pregnancy & Breastfeeding
• Urea Emulsion Support Group
• 9 Reviews for Urea - Add your own review/rating

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Estraderm MX 25

1. Name Of The Medicinal Product

Estraderm MX^® 25

2. Qualitative And Quantitative Composition

The active ingredient is estra-1, 3,5(10)-triene-3,17ß-diol (estradiol hemihydrate).

Patches contain 0.75 mg active substance corresponding to a surface area of 11cm².

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Estraderm MX is a square-shaped, self-adhesive, transparent, transdermal patch for application to the skin surface. Each patch comprises an impermeable polyester backing film, an adhesive matrix containing estradiol and an oversized protective liner which is removed prior to application of the patch to the skin. Estraderm MX releases estradiol into the circulation via intact skin at a low rate for up to 4 days.

Cross section:

DOSAGE STRENGTHS	ESTRADERM MX 25
Nominal rate of estradiol release	25 micrograms /day
Estradiol content	0.75mg
Drug-releasing area	11 cm²
Imprint (on backing film)	Product logo CG GRG

4. Clinical Particulars

4.1 Therapeutic Indications

Hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women.

(See also section 4.4)

The experience treating women older than 65 years is limited.

4.2 Posology And Method Of Administration

Estraderm MX 25 is an estrogen only patch.

In women with an intact uterus estrogen should be supplemented by sequential administration of a progestogen (e.g. medroxyprogesterone acetate 10mg, norethisterone 5mg, norethisterone acetate 1-5mg or dydrogesterone 20mg per day) to be taken at least on the last 12 days of each 4-week treatment cycle. Withdrawal bleeding usually occurs following 12 days or more of progesterone administration. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.

Dosage

Adults and Elderly

Menopausal symptoms: For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used (see also section 4.4). Depending on the clinical response the dose can then be adjusted to the patient's individual needs. If, after three months, there is insufficient response in the form of alleviated symptoms, the dose can be increased. A maximum dose of 100 micrograms per day should not be exceeded.

Effects usually of estrogenic origin e.g. breast discomfort, water retention or bloating are often observed at the start of treatment, especially in patients receiving hormone replacement therapy for the first time. However, if symptoms persist for more than six weeks the dose should be reduced.

General instructions: Estraderm MX is administered as a continuous treatment (uninterrupted application twice weekly).

For most postmenopausal women not taking HRT Estraderm MX therapy may be started at any convenient time. However, for women with an intact uterus who are still menstruating regularly, commencement within 5 days of the onset of bleeding is recommended.

In women with an intact uterus transferring from a continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen.

In women transferring from a continuous-combined HRT regimen, or hysterectomised women transferring from other estrogen-only HRT treatment, treatment may be started on any convenient day.

Administration: Estraderm MX should be applied immediately after removal of the protective liner (see Figs.), to an area of clean, dry, and intact skin on the trunk below the waistline. The site chosen should be one at which little wrinkling of skin occurs during movement of the body, e.g. buttock. Estraderm MX should never be applied to, or near the breasts.

Estraderm MX should be applied twice weekly on a continuous basis, each used patch being removed after 3-4 days and a fresh system applied to a slightly different site.

If a woman has forgotten to apply a patch, she should apply a new patch as soon as possible. The subsequent patch should be applied according to the original treatment schedule. The interruption of treatment might increase the likelihood of recurrence of symptoms and include breakthrough spotting and bleeding.

In the event that a patch should fall off a new patch may be applied. The original treatment schedule should be continued.

The patch should not be exposed to sunlight.

Children

Estraderm MX should not be used in children.

4.3 Contraindications

Estraderm MX should not be used by women with any of the following conditions:

• Known, past or suspected breast cancer

• Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer)

• Undiagnosed genital bleeding

• Untreated endometrial hyperplasia

• Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)

• Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)

• Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal

• Known hypersensitivity to the active substance or to any of the excipients

• Porphyria

4.4 Special Warnings And Precautions For Use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

Medical Examination / follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Estraderm MX, in particular:

• Leiomyoma (uterine fibroids) or endometriosis

• A history of, or risk factors for, thromboembolic disorders (see below)

• Risk factors for estrogen dependent tumours, e.g. 1^st degree heredity for breast cancer

• Hypertension

• Liver disorders (e.g. liver adenoma)

• Diabetes mellitus with or without vascular involvement

• Cholelithiasis

• Migraine or (severe) headache

• Systemic lupus erythematosus

• A history of endometrial hyperplasia (see below)

• Epilepsy

• Asthma

• Otosclerosis

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

• Jaundice or deterioration in liver function

• Significant increase in blood pressure

• New onset of migraine-type headache

• Pregnancy

Endometrial hyperplasia

The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk. Withdrawal bleeding usually occurs following the 12 days or more of progestagen administration.

Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestagens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.

Breast cancer

A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestagen combinations or tibolone for HRT for several years (see section 4.8 ).

For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

HRT, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Venous thromboembolism

HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism.

One randomised controlled trial and epidemiological studies found a 2-3 fold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

Generally recognised risk factors for VTE include a personal history or family history, severe obesity (Body Mass Index > 30kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the role of varicose veins in VTE.

Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contra-indicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all post-operative patients scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT four to six weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.

If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

HRT should not be used to prevent cardiovascular disease.

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Large clinical trials showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there only limited data from randomised controlled trials examining effect on cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years , the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer

Long-term (at least 5 to 10 years) use of estrogen–only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.

Angioedema

Estrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.

Other conditions

Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Estraderm MX is increased.

Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin). These effects may be less common with transdermal estradiol than with oral estrogens.

Contact sensitisation is known to occur with all topical applications. Although it is extremely rare, patients who develop contact sensitisation to any of the components of the patch should be warned that a severe hypersensitivity reaction may occur with continuous exposure to the causative agent.

Although observations to date suggest that estrogens, including transdermal estradiol, do not impair carbohydrate metabolism, diabetic women should be monitored during initiation of therapy until further information is available.

Thyroid function should be monitored regularly in patients who require thyroid hormone replacement therapy and who are also taking estrogen in order to ensure that thyroid hormone levels remain within an acceptable range.

Women should be advised that Estraderm MX is not a contraceptive, nor will it restore fertility. Women requiring contraception should be advised to use non-hormonal contraception.

There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger postmenopausal women or other HRT products.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of estrogens and progestagens.

With transdermal HRT administration, the first-pass effect in the liver is avoided and, thus transdermally applied estrogens may be less affected by enzyme inducers than oral hormones.

Clinically, an increased metabolism of estrogens and progestagens may lead to decreased effects and changes in the uterine bleeding profile.

Some laboratory tests may be influenced by estrogen therapy, such as tests for glucose tolerance or thyroid function.

4.6 Pregnancy And Lactation

Pregnancy

Estraderm MX is not indicated during pregnancy. If pregnancy occurs during medication with Estraderm MX treatment should be withdrawn immediately.

The results of most epidemiological studies to date relevant to inadvertant foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.

Lactation

Estraderm MX is not indicated during lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Organ system class (e.g. MedDRA SOC level)	Common ADRS	Uncommon ADRs	Rare ADRs
Central nervous system	Headache.		Dizziness
Cardiovascular Disorders			Thromboembolic disorders, exacerbation of varicose veins, hypertension
Gastrointestinal disorder	Nausea, abdominal cramps, bloating		Abnormal liver function tests, cholestatic jaundice.
Skin and subcutaneous tissue disorders	Transient erythema and irritation at the site of application with or without pruritis		Contact dermatitis, pigmentation disorders, generalised pruritis and exanthema.
Reproductive system and breast disorders	Breast discomfort, breakthrough bleeding	*breast cancer
General disorders			Oedema and/or weight changes, leg pain, Anaphylactoid reactions

*Breast Cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 - 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

For estrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

The MWS reported that, compared to never users, the use of various types of estrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be:

• For users of estrogen-only replacement therapy

• between 0 and 3 (best estimate = 1.5) for 5 years' use • between 3 and 7 (best estimate = 5) for 10 years' use.

• For users of estrogen plus progestagen combined HRT

• between 5 and 7 (best estimate = 6) for 5 years' use • between 18 and 20 (best estimate = 19) for 10 years' use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years.

According to calculations from the trial data, it is estimated that:

• For 1000 women in the placebo group,

• about 16 cases of invasive breast cancer would be diagnosed in 5 years.

• For 1000 women who used estrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be

• between 0 and 9 (best estimate = 4) for 5 years' use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk of endometrial cancer is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2- to 12-fold greater compared with non-users. Adding a progestagen to estrogen-only therapy greatly reduces this increased risk.

Other adverse reactions have been reported in association with estrogen alone and estrogen-progestagen treatments:

• Estrogen-dependent neoplasms, benign and malignant, e.g. endometrial cancer

• Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use

• Myocardial infarction and stroke

• Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura

• Gall bladder disease

• Probable dementia (see section 4.4)

4.9 Overdose

This is not likely due to the mode of administration.

Signs and Symptoms: Signs of acute estrogen overdosage may be either one of, or a combination of, breast discomfort, fluid retention and bloating or nausea.

Treatment: Overdosage can if necessary be reversed by removal of the patch(es).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: estrogens ATC code G 03 C A 03.

The active ingredient, synthetic 17β-estradiol is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms.

5.2 Pharmacokinetic Properties

Absorption

Steady-state serum oestradiol concentrations are reached within 8 hours after application of Estraderm MX 50 to the skin, and remain stable during 4 days. The mean E2 concentration during steady-state of Estraderm MX 50 is 41 pg/mL in healthy postmenopausal women, corresponding to a mean increase of 37 pg/mL over the mean baseline value of 4 pg/mL (range 2.1 to 9.0 pg/mL). The E2:E1 ratio increases from a postmenopausal value of 0.3 to a value of 1.3, similar to the physiological ratio of E2 to E1 observed before the menopause in women with normally functioning ovaries. During continuous treatment of postmenopausal women with Estraderm MX 50 twice weekly for 12 weeks, mean E2 plasma concentrations rise by 36 pg/mL above baseline at the end of the treatment phase, without any indication that accumulation of E2 levels occurs.

With Estraderm MX 25, E2 plasma levels half those observed with Estraderm MX 50 are measured, and with Estraderm MX 100 plasma E2 levels are slightly more than double those measured with Estraderm MX 50 .

Plasma oestradiol concentrations return to baseline value within 24 hours after removal of the patch.

Distribution

In plasma, oestradiol is largely bound to sex hormone binding globulin (SHBG) and albumin. Only a fraction is free and biologically active.

Metabolism

Transdermally applied oestradiol is metabolised in the same way as the endogenous hormone. Oestradiol is metabolised to oestrone, then later – primarily in the liver – to oestriol, epioestriol and catechol oestrogens, which are then conjugated to sulphates and glucoronides. Cytochrome 450 isoforms CYP1A2 and CYP3A4 catalyse the hydroxylation of oestradiol forming oestriol. Oestriol is glucuronidated by UGT1A1 and UGT2B7 in humans. Metabolic plasma clearance ranges from 650 to 900 L/(day x m²). Oestradiol metabolites are also subject to enterohepatic circulation. Oestradiol metabolites are far less active than oestradiol.

Elimination

Oestradiol and its metabolites are mainly excreted in the urine. The plasma elimination half-life of oestradiol is about 1 hour. Oestradiol conjugates excreted in the urine return to pre-application levels on the second or third day after removal of the system.

5.3 Preclinical Safety Data

Animal studies with estradiol have only shown effects which can be expected from an estrogenic substance.

Acute toxicity of estrogens is low. Because of marked differences between animal species and between animals and humans, preclinical results possess a limited predictive value for the application of estrogens in humans.

In experimental animals estradiol displayed an embryolethal effect at relatively low doses; malformations of the urogenital tract and feminisation of male foetuses were observed.

Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Acrylate, methacrylate, isopropyl palmitate, polyethylene terephthalate, ethylenevinylacetate copolymer, silicone coating (on the inner side of the protective release liner which is removed before patch application).

6.2 Incompatibilities

None known

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store below 25°C.

Keep out of the reach of children both before and after use.

6.5 Nature And Contents Of Container

Each system is individually heat sealed in a paper/aluminium/polyethylene foil pouch. Eight or twenty four Estraderm MX pouches are placed in an appropriately sized carton which comprises the finished product (one or three month's treatment respectively).

6.6 Special Precautions For Disposal And Other Handling

See Section 4.2. Exposure of Estraderm MX patches to ultra-violet light results in degradation of estradiol. Patches should not be exposed to sunlight. They should be applied immediately after removal from the pouch to skin sites covered by clothing.

After use, the Estraderm MX patch should be folded (adhesive surfaces pressed together) and discarded in such a way as to keep them out of the reach and sight of children.

7. Marketing Authorisation Holder

Novartis Pharmaceuticals UK Ltd

Trading as Ciba Laboratories

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

8. Marketing Authorisation Number(S)

PL 0101/0486

9. Date Of First Authorisation/Renewal Of The Authorisation

12 September 1997 / 10 February 2009

10. Date Of Revision Of The Text

19 May 2011

LEGAL CATEGORY

POM