Best Articles Directory Barbados: August 2012

Friday, 31 August 2012

Caverject

alprostadil

Dosage Form: injection
Caverject IMPULSE®

Dual Chamber System

alprostadil for injection

For Intracavernosal Use

Caverject Description

Caverject contains alprostadil as the naturally occurring form of prostaglandin E1 (PGE1) and is designated chemically as (11α,13E,15S)-11,15-dihydroxy-9-oxoprost-13-en-1-oic acid. The molecular weight is 354.49.

Alprostadil is a white to off-white crystalline powder with a melting point between 115° and 116°C. Its solubility at 35°C is 8000 micrograms (mcg) per 100 milliliter double distilled water.

The structural formula of alprostadil is represented below:

Caverject IMPULSE is available as a disposable, single-dose, dual chamber syringe system. The system includes a glass cartridge which contains sterile, freeze-dried alprostadil in the front chamber and sterile bacteriostatic water for injection in the rear chamber. The alprostadil is reconstituted with the sterile bacteriostatic water just before injection. Caverject IMPULSE is available in two strengths for intracavernosal administration:

10 microgram – The reconstituted solution has a volume of 0.64 mL. The delivered volume, 0.5 mL, contains 10 micrograms (mcg) of alprostadil, 324.7 mcg of alpha cyclodextrin, 45.4 mg of lactose, 23.5 mcg of sodium citrate, and 4.45 mg of benzyl alcohol.

20 microgram – The reconstituted solution has a volume of 0.64 mL. The delivered volume, 0.5 mL, contains 20 micrograms (mcg) of alprostadil, 649.3 mcg of alpha cyclodextrin, 45.4 mg of lactose, 23.5 mcg of sodium citrate, and 4.45 mg of benzyl alcohol.

When necessary, the pH of the alprostadil for injection was adjusted with hydrochloric acid and/or sodium hydroxide before lyophilization.

Caverject - Clinical Pharmacology

Alprostadil has a wide variety of pharmacological actions; vasodilation and inhibition of platelet aggregation are among the most notable of these effects. In most animal species tested, alprostadil relaxed retractor penis and corpus cavernosum urethrae in vitro. Alprostadil also relaxed isolated preparations of human corpus cavernosum and spongiosum, as well as cavernous arterial segments contracted by either noradrenaline or PGF2a in vitro. In pigtail monkeys (Macaca nemestrina), alprostadil increased cavernous arterial blood flow in vivo. The degree and duration of cavernous smooth muscle relaxation in this animal model was dose-dependent.

Alprostadil induces erection by relaxation of trabecular smooth muscle and by dilation of cavernosal arteries. This leads to expansion of lacunar spaces and entrapment of blood by compressing the venules against the tunica albuginea, a process referred to as the corporal veno-occlusive mechanism.

Pharmacokinetics

Absorption

For the treatment of erectile dysfunction, alprostadil is administered by injection into the corpora cavernosa. The absolute bioavailability of alprostadil has not been determined.

Distribution

Following intracavernosal injection of 20 mcg alprostadil, mean peripheral plasma concentrations of alprostadil at 30 and 60 minutes after injection (89 and 102 picograms/mL, respectively) were not significantly greater than baseline levels of endogenous alprostadil (96 picograms/mL). Plasma levels of alprostadil were measured using a radioimmunoassay method. Alprostadil is bound in plasma primarily to albumin (81% bound) and to a lesser extent I-globulin IV-4 fraction (55% bound). No significant binding to erythrocytes or white blood cells was observed.

Metabolism

Alprostadil is rapidly converted to compounds, which are further metabolized prior to excretion. Following intravenous administration, approximately 80% of circulating alprostadil is metabolized in one pass through the lungs, primarily by beta- and omega-oxidation. Hence, any alprostadil entering the systemic circulation following intracavernosal injection is very rapidly metabolized. Following intracavernosal injection of 20 mcg alprostadil, peripheral levels of the major circulating metabolite, 13,14-dihydro-15-oxo-PGE1, increased to reach a peak 30 minutes after injection and returned to pre-dose levels by 60 minutes after injection.

Excretion

The metabolites of alprostadil are excreted primarily by the kidney, with almost 90% of an administered intravenous dose excreted in urine within 24 hours post-dose. The remainder of the dose is excreted in the feces. There is no evidence of tissue retention of alprostadil or its metabolites following intravenous administration.

Pharmacokinetics in Special Populations

Geriatric

The potential effect of age on the pharmacokinetics of alprostadil has not been formally evaluated. In patients with acute respiratory distress syndrome (ARDS), the mean (± SD) pulmonary extraction of alprostadil was 72% ± 15% in 11 elderly patients aged 65 years or older (mean, 71 ± 6 years) and 65% ± 20% in 6 young patients aged 35 years or younger (mean, 28 ± 5 years).

Pediatric

Alprostadil plasma concentrations were measured in 10 neonates (gestational age of 34 weeks in 2 infants and 38 to 40 weeks in 8 infants) receiving steady-state intravenous infusions of alprostadil to treat underlying cardiac malformations. Infusion rates of alprostadil ranged from 5 to 50 (median, 45) nanograms/kilogram/minute, resulting in alprostadil plasma concentrations ranging between 22 and 530 (median, 56) picograms/mL. The wide range of alprostadil plasma concentrations in neonates reflects high variability in individual clearances of alprostadil in this patient population.

Gender

The potential influence of gender on the pharmacokinetics of alprostadil has not been formally studied in healthy subjects. Two studies determined the pulmonary extraction of alprostadil following intravascular administration in 23 patients with ARDS. The mean (± SD) pulmonary extraction was 66% ± 20% in 17 male patients and 69% ± 18% in 6 female patients, suggesting that the pharmacokinetics of alprostadil are not influenced by gender.

Race

The potential influence of race in the pharmacokinetics of alprostadil has not been formally evaluated.

Renal and Hepatic Insufficiency

The pharmacokinetics of alprostadil have not been formally studied in patients with renal or hepatic insufficiency.

Pulmonary Disease

The pulmonary extraction of alprostadil following intravascular administration was reduced by 15% (66 ± 3.2% vs. 78 ± 2.4%) in patients with ARDS compared with a control group of patients with normal respiratory function who were undergoing cardiopulmonary bypass surgery. Pulmonary clearance was found to vary as a function of cardiac output and pulmonary intrinsic clearance in a group of 14 patients with ARDS or at risk of developing ARDS following trauma or sepsis. In this study, the extraction efficiency of alprostadil ranged from subnormal (11%) to normal (90%), with an overall mean of 67%.

Drug-Drug Interactions

The potential for pharmacokinetic drug-drug interactions between alprostadil and other agents has not been formally studied.

Clinical Studies

The safety and efficacy of Caverject Sterile Powder was investigated in men with a diagnosis of erectile dysfunction due to psychogenic, vasculogenic, neurogenic, and/or mixed etiology in two well-controlled studies (Study 1 and Study 2) and in one 6-month open-label study (Study 3).

Study 1: One hundred fifty-three men with a mean age of 53 years (range 23–69 years) were enrolled. The study had three phases: a 2.5 week double-blind, in-office randomized crossover phase in which each man received placebo or 2.5 mcg, 5 mcg, 7.5 mcg, or 10 mcg of Caverject Sterile Powder; a 2 week open-label, in-office dose-titration phase to identify the optimum home-use dose (the latter dose was defined as a dose inducing an erection sufficient for penetration and lasting ≤ 60 minutes); and a 4-week open-label, self-injection phase. In the double-blind phase, each dose of Caverject was significantly more effective than placebo by clinical evaluation ("full penile rigidity") and by RigiScan criteria (≥ 70% rigidity for at least 10 minutes); there was no response to placebo. The percentage of responders increased with increasing doses of Caverject. The overall response in the dose-ranging phases was 76% (117/153) by clinical evaluation and 51% (78/152) by RigiScan criteria. The optimum dose for self-injection ranged from 1.25 to 65 mcg (median 20 mcg). Seventy-three percent of the injections in 102 men who self-injected Caverject resulted in satisfactory intercourse. Seventy-five percent of the patients remained on the dose identified during the dose-ranging phase; 17% and 8% of the patients slightly decreased or increased the dose, respectively. The mean duration of erection per injection was 70.8 minutes.

Study 2: Two hundred ninety-six men with a mean age of 53.8 years (range 21–74 years) were enrolled in this parallel-design, double-blind study. The men were randomly assigned to one of five groups and received either a single dose of placebo, 2.5 mcg, 5 mcg, 10 mcg, or 20 mcg of Caverject Sterile Powder. No patient responded to placebo. The differences in the response rates in both the clinical and the RigiScan evaluations between each of the doses of Caverject and placebo were statistically significant. There was also a statistically significant dose-response relationship with higher clinical response rates and higher RigiScan response rates with increasing doses of Caverject (with exception of the 10-mcg dose). The mean duration of erection after injection ranged from 12 minutes after the 2.5-mcg dose to 44 minutes after the 20-mcg dose and the relationship was linear (p = .025, linear regression analysis).

Study 3: The safety and efficacy of Caverject Sterile Powder was evaluated in a 6-month, open-label study in 683 men with a mean age of 58 years (range 20–79 years). The optimum dose of Caverject was established by titration in 89% of men (606/683). Four hundred seventy-one men (69%) completed the 6-month study. At the start of the study, the mean dose was 17.7 mcg of Caverject and at the end of the study it was 20.7 mcg. Eighty-seven percent of the 13,762 injections of Caverject, administered by self-injection by the men in the study, resulted in satisfactory sexual activity. The mean duration of erection was 67.5 minutes.

The formulation of alprostadil contained in Caverject IMPULSE includes the inactive excipient alpha cyclodextrin. This formulation was compared with Caverject Sterile Powder in 87 men in a single-blind, crossover study designed to evaluate efficacy and safety. The doses used by the patients in the study ranged from 2.5 mcg to 20 mcg and were the same for both formulations. The efficacy of the two formulations was shown to be comparable, as assessed by the 30-point erectile function (EF) domain score from the International Index of Erectile Function (IIEF) and by a physician-assessment score for erectile response. The mean EF domain scores for Caverject Sterile Powder and the formulation contained in Caverject IMPULSE were 26.6 (SD=5.3) and 27.6 (SD=3.8), respectively. The mean physician's assessment scores for Caverject Sterile Powder and the formulation contained in Caverject IMPULSE were 2.6 (SD=0.6) and 2.7 (SD=0.5), respectively, based on a scale of 0 (no tumescence) to 3 (full rigidity).

INDICATION AND USAGE

Caverject (Caverject IMPULSE, Caverject Sterile Powder, and Caverject Injection) is indicated for the treatment of erectile dysfunction due to neurogenic, vasculogenic, psychogenic, or mixed etiology.

Intracavernosal Caverject is also indicated as an adjunct to other diagnostic tests in the diagnosis of erectile dysfunction.

Contraindications

Caverject should not be used in patients who have a known hypersensitivity to the drug, in patients who have conditions that might predispose them to priapism, such as sickle cell anemia or trait, multiple myeloma, or leukemia, or in patients with anatomical deformation of the penis, such as angulation, cavernosal fibrosis, or Peyronie's disease. Patients with penile implants should not be treated with Caverject.

Caverject is intended for use in adult men only.

Caverject is not indicated for use in children or newborns.

Caverject should not be used in men for whom sexual activity is inadvisable or contraindicated.

Warnings

Prolonged erection defined as erection lasting > 4 to ≤ 6 hours in duration occurred in 4% of 1,861 patients treated up to 18 months in studies of Caverject Sterile Powder. The incidence of priapism (erections lasting > 6 hours in duration) was 0.4% with the same length of use. Pharmacologic intervention and/or aspiration of blood from the corpora cavernosum was performed in 2 of the 7 patients with priapism. To minimize the chances of prolonged erection or priapism, Caverject should be titrated slowly to the lowest effective dose (see DOSAGE AND ADMINISTRATION). The patient must be instructed to immediately report to his prescribing physician, or, if unavailable, to seek immediate medical assistance for any erection that persists longer than 4 hours. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Precautions

General Precautions

Caverject IMPULSE is designed for one use only. Following a single use, the injection device and any remaining solution should be properly discarded.

The overall incidence of penile fibrosis, including Peyronie's disease, reported in clinical studies with Caverject Sterile Powder was 3%. In one self-injection clinical study where duration of use was up to 18 months, the incidence of fibrosis was 7.8%.

Regular follow-up of patients, with careful examination of the penis, is strongly recommended to detect signs of penile fibrosis. Treatment with Caverject should be discontinued in patients who develop penile angulation, cavernosal fibrosis, or Peyronie's disease.

Intracavernous injections of Caverject can lead to increased peripheral blood levels of PGE1 and its metabolites, especially in those patients with significant corpora cavernosa venous leakage. Increased peripheral blood levels of PGE1 and its metabolites may lead to hypotension and/or dizziness.

Patients on anticoagulants, such as warfarin or heparin, may have increased propensity for bleeding after intracavernosal injection.

Underlying treatable medical causes of erectile dysfunction should be diagnosed and treated prior to initiation of therapy with Caverject.

The safety and efficacy of combinations of Caverject and other vasoactive agents have not been systematically studied. Therefore, the use of such combinations is not recommended.

Caverject IMPULSE uses a superfine (29 gauge) needle. As with all superfine needles, the possibility of needle breakage exists. Careful instruction in proper patient handling and injection techniques may minimize the potential for needle breakage.

The patient should be instructed not to re-use or to share needles or syringes. As with all prescription medicines, the patient should not allow anyone else to use his medicine.

Information for the Patient

To ensure safe and effective use of Caverject, the patient should be thoroughly instructed and trained in the self-injection technique before he begins intracavernosal treatment with Caverject at home. The desirable dose should be established in the physician's office.

Any reconstituted solution with precipitates or discoloration should be discarded. The Caverject IMPULSE syringe system is designed for one use only and should be discarded after use. The device and the needle must be properly discarded after use. Needles must not be re-used or shared with other persons. Patient instructions for administration are included in each package of Caverject IMPULSE.

The dose of Caverject that is established in the physician's office should not be changed by the patient without consulting the physician. The patient may expect an erection to occur within 5 to 20 minutes. A standard treatment goal is to produce an erection lasting no longer than 1 hour. Generally, Caverject should be used no more than 3 times per week, with at least 24 hours between each use.

Patients should be aware of possible side effects of therapy with Caverject; the most frequently occurring is penile pain after injection, usually mild to moderate in severity. A potentially serious adverse reaction with intracavernosal therapy is priapism. Accordingly, the patient should be instructed to contact the physician's office immediately or, if unavailable, to seek immediate medical assistance if an erection persists for longer than 4 hours.

The patient should report any penile pain that was not present before or that increased in intensity, as well as the occurrence of nodules or hard tissue in the penis to his physician as soon as possible. As with any injection, an infection is a possibility. Patients should be instructed to report to the physician any penile redness, swelling, tenderness or curvature of the erect penis. The patient must visit the physician's office for regular check-ups for assessment of the therapeutic benefit and safety of treatment with Caverject.

Note: Use of intracavernosal Caverject offers no protection from the transmission of sexually transmitted diseases. Individuals who use Caverject should be counseled about the protective measures that are necessary to guard against the spread of sexually transmitted diseases, including the human immunodeficiency virus (HIV).

The injection of Caverject can induce a small amount of bleeding at the site of injection (see ADVERSE REACTIONS section hematoma, ecchymosis, hemorrhage at the site of injection). In patients infected with blood-borne diseases, this could increase the risk of transmission of blood-borne diseases between partners.

In clinical trials, concomitant use of agents such as antihypertensive drugs, diuretics, antidiabetic agents (including insulin), or non-steroidal anti-inflammatory drugs had no effect on the efficacy or safety of Caverject.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term carcinogenicity studies have not been conducted. Rat reproductive studies indicate that alprostadil at doses of up to 0.2 mg/kg/day does not adversely affect or alter rat spermatogenesis, providing a 200-fold margin of safety compared with the usual human doses. The following battery of mutagenicity assays revealed no potential for mutagenesis: bacterial mutation (Ames), alkaline elution, rat micronucleus, sister chromatid exchange, CHO/HGPRT mammalian cell forward gene mutation, and unscheduled DNA synthesis (UDS).

A 1-year irritancy study was conducted in three groups of 5 male Cynomolgus monkeys injected intracavernosally twice weekly with either vehicle or 3 or 8.25 mcg of alprostadil/ injection. An additional two groups of 6 monkeys each were injected with vehicle or with 8.25 mcg/injection twice weekly as described previously plus they received multiple doses during weeks 44, 48, and 52. Three monkeys from each group were retained for a 4-week recovery period. There was no evidence of drug-related penile irritancy or nonpenile tissue lesions, which could be directly related to alprostadil. The irritancy, which was noted for control and treated monkeys, was considered to be a result of the injection procedure itself, and any lesions noted were shown to be reversible. At the end of the 4-week recovery period, the histological changes in the penis had regressed.

Pregnancy, Nursing Mothers, and Pediatric Use

Caverject is not indicated for use in pediatric patients or women.

Geriatric Use

A total of 341 subjects included in clinical studies were 65 and older. No overall differences in safety and effectiveness were observed between these subjects and younger subjects, and the other reported clinical experience has not identified differences in responses between elderly and younger patients, but decreased sensitivity of some older individuals cannot be ruled out.

Adverse Reactions

Local Adverse Reactions

The following local adverse reaction information was derived from controlled and uncontrolled studies of Caverject Sterile Powder, including an uncontrolled 18-month safety study.

Local Adverse Reactions Reported by ≥ 1% of Patients Treated with Caverject Sterile Powder for up to 18 Months*
Event	Caverject N = 1861
* Except for penile pain (2%), no significant local adverse reactions were reported by 294 patients who received 1 to 3 injections of placebo. † See General Precautions. ‡ Includes numbness, yeast infection, irritation, sensitivity, phimosis, pruritus, erythema, venous leak, penile skin tear, strange feeling of penis, discoloration of penile head, itch at tip of penis.
Penile pain	37%
Prolonged erection	4%
Penile fibrosis†	3%
Injection site hematoma	3%
Penis disorder‡	3%
Injection site ecchymosis	2%
Penile rash	1%
Penile edema	1%

Penile Pain

Penile pain after intracavernosal administration of Caverject was reported at least once by 37% of patients in clinical studies of up to 18 months in duration. In the majority of the cases, penile pain was rated mild or moderate in intensity. Three percent of patients discontinued treatment because of penile pain. The frequency of penile pain was 2% in 294 patients who received 1 to 3 injections of placebo.

Prolonged Erection/Priapism

In clinical trials, prolonged erection was defined as an erection that lasted for 4 to 6 hours; priapism was defined as erection that lasted 6 hours or longer. The frequency of prolonged erection after intracavernosal administration of Caverject was 4%, while the frequency of priapism was 0.4% (see WARNINGS).

Hematoma/Ecchymosis

The frequency of hematoma and ecchymosis was 3% and 2%, respectively. In most cases, hematoma/ecchymosis was judged to be a complication of a faulty injection technique. Accordingly, proper instruction of the patient in self-injection is of importance to minimize the potential of hematoma/ecchymosis (see DOSAGE AND ADMINISTRATION).

The following local adverse reactions were reported by fewer than 1% of patients after injection of Caverject: balanitis, injection site hemorrhage, injection site inflammation, injection site itching, injection site swelling, injection site edema, urethral bleeding, penile warmth, numbness, yeast infection, irritation, sensitivity, phimosis, pruritus, erythema, venous leak, painful erection, and abnormal ejaculation.

Systemic Adverse Events

The following systemic adverse event information was derived from controlled and uncontrolled studies of Caverject Sterile Powder, including an uncontrolled 18-month safety study.

Systemic Adverse Events Reported by ≥ 1% of Patients Treated with Caverject Sterile Powder for up to 18 Months*
Body System/Reaction	Caverject N = 1861
* No significant adverse events were reported by 294 patients who received 1 to 3 injections of placebo. † Prostatitis, pain, hypertrophy, enlargement ‡ Pain in various anatomical structures other than injection site § Injuries, fractures, abrasions, lacerations, dislocations
Cardiovascular System
Hypertension	2%
Central Nervous System
Headache	2%
Dizziness	1%
Musculoskeletal System
Back pain	1%
Respiratory System
Upper respiratory infection	4%
Flu syndrome	2%
Sinusitis	2%
Nasal congestion	1%
Cough	1%
Urogenital System
Prostatic Disorder†	2%
Miscellaneous
Localized pain‡	2%
Trauma§	2%

The following systemic events, which were reported for < 1% of patients in clinical studies, were judged by investigators to be possibly related to use of Caverject: testicular pain, scrotal disorder, scrotal edema, hematuria, testicular disorder, impaired urination, urinary frequency, urinary urgency, pelvic pain, hypotension, vasodilation, peripheral vascular disorder, supraventricular extrasystoles, vasovagal reactions, hypesthesia, non-generalized weakness, diaphoresis, rash, non-application site pruritus, skin neoplasm, nausea, dry mouth, increased serum creatinine, leg cramps, and mydriasis.

Hemodynamic changes, manifested as decreases in blood pressure and increases in pulse rate, were observed during clinical studies, principally at doses above 20 mcg and above 30 mcg of alprostadil, respectively, and appeared to be dose-dependent. However, these changes were usually clinically unimportant; only three patients discontinued the treatment because of symptomatic hypotension.

Caverject had no clinically important effect on serum or urine laboratory tests.

The safety of Caverject IMPULSE was evaluated in a study that compared the formulation of alprostadil for injection contained in Caverject IMPULSE with the formulation contained in Caverject Sterile Powder. The doses used by the 87 patients in this crossover study were the same for both formulations. The number and type of events reported for Caverject IMPULSE were consistent between formulations in this study and in other controlled and uncontrolled studies with Caverject Sterile Powder.

Overdosage

Overdosage was not observed in clinical trials with Caverject. If intracavernous overdose of Caverject occurs, the patient should be under medical supervision until any systemic effects have resolved and/or until penile detumescence has occurred. Symptomatic treatment of any systemic symptoms would be appropriate.

Caverject Dosage and Administration

The dose of Caverject should be individualized for each patient by careful titration under supervision by the physician. In clinical studies, patients were treated with Caverject Sterile Powder in doses ranging from 0.2 to 140 mcg; however, since 99% of patients received doses of 60 mcg or less, doses of greater than 60 mcg are not recommended. In general, the lowest possible effective dose should always be employed. In clinical studies, over 80% of patients experienced an erection sufficient for sexual intercourse after intracavernosal injection of Caverject.

Initial Titration in Physician's Office

Erectile Dysfunction of Vasculogenic, Psychogenic, or Mixed Etiology

Dosage titration should be initiated at 2.5 mcg of alprostadil. The 10 mcg strength of Caverject IMPULSE is designed to allow delivery of a 2.5 mcg dose of alprostadil (see General Procedure for Solution Preparation). If there is a partial response at 2.5 mcg, the dose may be increased by 2.5 mcg to a dose of 5 mcg within 1 hour. No more than 2 doses during initial titration should be given within a 24-hour period. If additional titration is required, doses in increments of 5 to 10 mcg may be given at least 24 hours apart until the dose that produces an erection suitable for intercourse and not exceeding a duration of 1 hour is reached. If there is no response to the initial 2.5-mcg dose, the second dose may be increased to 7.5 mcg within 1 hour. No more than 2 doses during initial titration should be given within a 24-hour period. If additional titration is required, doses in increments of 5 to 10 mcg may be given at least 24 hours apart. The patient must stay in the physician's office until complete detumescence occurs.

Erectile Dysfunction of Pure Neurogenic Etiology (Spinal Cord Injury)

Dosage titration should be initiated at 1.25 mcg of alprostadil. Because Caverject IMPULSE is designed to deliver doses of 2.5 mcg or greater (see General Procedure for Solution Preparation), Caverject Sterile Powder or Caverject Injection may be used for an initial dose of 1.25 mcg. The initial dose may be increased by 1.25 mcg to a dose of 2.5 mcg within 1 hour. No more than 2 doses during initial titration should be given within a 24-hour period. If additional titration is required, a dose of 5 mcg may be given during the next 24 hours. Thereafter, doses in increments of 5 mcg may be given at least 24 hours apart until the dose that produces an erection suitable for intercourse and not exceeding a duration of 1 hour is reached. The patient must stay in the physician's office until complete detumescence occurs.

The majority of patients (56%) in one clinical study involving 579 patients with erectile dysfunction of various etiologies were titrated to doses of greater than 5 mcg but less than or equal to 20 mcg. The mean dose at the end of the titration phase was 17.8 mcg of alprostadil.

Maintenance Therapy

The first injections of Caverject must be done at the physician's office by medically trained personnel. Self-injection therapy by the patient should be started only after the patient is properly instructed and well trained in the self-injection technique. The physician should make a careful assessment of the patient's skills and competence with this procedure. The intracavernosal injection must be done under sterile conditions. The site of injection is usually along the dorso-lateral aspect of the proximal third of the penis. Visible veins should be avoided. The side of the penis that is injected and the site of injection must be alternated; the injection site must be cleansed with an alcohol swab.

The dose of Caverject that is selected for self-injection treatment should provide the patient with an erection that is satisfactory for sexual intercourse and that is maintained for no longer than 1 hour. If the duration of erection is longer than 1 hour, the dose of Caverject should be reduced. Self-injection therapy for use at home should be initiated at the dose that was determined in the physician's office; however, dose adjustment, if required (up to 57% of patients in one clinical study), should be made only after consultation with the physician. The dose should be adjusted in accordance with the titration guidelines described above. The effectiveness of Caverject for long-term use of up to 6 months has been documented in an uncontrolled, self-injection study. The mean dose of Caverject Sterile Powder at the end of 6 months was 20.7 mcg in this study. Caverject IMPULSE in the 10 mcg strength is designed to deliver a minimum dose of 2.5 mcg and a maximum dose of 10 mcg. Caverject IMPULSE in the 20 mcg strength is designed to deliver a minimum dose of 5 mcg and a maximum dose of 20 mcg. The physician should determine the most suitable formulation of Caverject for the individual patient (Caverject IMPULSE, Caverject Sterile Powder, or Caverject Injection).

Careful and continuous follow-up of the patient while in the self-injection program must be exercised. This is especially true for the initial self-injections, since adjustments in the dose of Caverject may be needed. The recommended frequency of injection is no more than 3 times weekly, with at least 24 hours between each dose. All formulations of Caverject are intended for single use only and should be discarded after use. The user should be instructed in the proper disposal of the injection materials (e.g., device, needles).

While on self-injection treatment, it is recommended that the patient visit the prescribing physician's office every 3 months. At that time, the efficacy and safety of the therapy should be assessed, and the dose of Caverject should be adjusted, if needed.

Caverject as an Adjunct to the Diagnosis of Erectile Dysfunction

In the simplest diagnostic test for erectile dysfunction (pharmacologic testing), patients are monitored for the occurrence of an erection after an intracavernosal injection of Caverject. Extensions of this testing are the use of Caverject as an adjunct to laboratory investigations, such as duplex or Doppler imaging, 133Xenon washout tests, radioisotope penogram, and penile arteriography, to allow visualization and assessment of penile vasculature. For any of these tests, a single dose of Caverject that induces an erection with firm rigidity should be used.

General Procedure for Solution Preparation

Caverject IMPULSE consists of a disposable, single-dose, dual chamber syringe system. The system includes a glass cartridge, which contains sterile, freeze-dried alprostadil in the front chamber and sterile bacteriostatic water for injection in the rear chamber. Following proper reconstitution instructions, the 10 mcg strength syringe can deliver up to 0.5 mL of solution. Each 0.5 mL of solution contains 10 mcg of alprostadil, 324.7 mcg of alpha cyclodextrin, 45.4 mg of lactose, 23.5 mcg of sodium citrate, and 4.45 mg of benzyl alcohol. The delivery device can be set to deliver a solution volume of 0.125, 0.25, 0.375, or 0.50 mL to enable administration of 2.5, 5, 7.5, or 10 mcg of alprostadil. Following proper reconstitution instructions, the 20 mcg strength syringe can deliver up to 0.5 mL of solution. Each 0.5 mL of solution contains 20 mcg of alprostadil, 649.3 mcg of alpha cyclodextrin, 45.4 mg of lactose, 23.5 mcg of sodium citrate, and 4.45 mg of benzyl alcohol. The delivery device can be set to deliver a solution volume of 0.125, 0.25, 0.375, or 0.50 mL to enable administration of 5, 10, 15, or 20 mcg of alprostadil. After reconstitution, the solution of Caverject should be used within 24 hours when stored at or below 25°C (77°F). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. The product should not be used if particulate matter or discoloration are present. Following a single use, the injection device and any remaining solution should be properly discarded.

Caution: Caverject IMPULSE is for single use only. Do not use any remaining Caverject solution.

How is Caverject Supplied

Caverject IMPULSE is supplied as a disposable, single-dose, dual chamber syringe system. The system includes a glass cartridge, which contains sterile, freeze-dried alprostadil in the front chamber and sterile bacteriostatic water for reconstitution in the rear chamber. The syringes contain either 12.8 or 25.6 mcg of alprostadil to allow delivery of a maximum of 10 or 20 mcg/0.5mL. Store the unreconstituted product at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

When reconstituted and used as directed, the deliverable amount for the 10 mcg strength is 10 mcg/0.5 mL or an increment of 10 mcg/0.5 mL, 2.5 mcg/0.125 mL, 5 mcg/0.25 mL, or 7.5 mcg/0.375 mL of alprostadil and the deliverable amount for the 20 microgram strength is 20 mcg/0.5 mL or an increment of 20 mcg/0.5 mL, 5 mcg/0.125 mL, 10 mcg/0.250 mL, or 15 mcg/0.375 mL of alprostadil. The reconstituted solution should be used within 24 hours when stored at or below 25°C (77°F).

Caverject IMPULSE is supplied in a carton containing 2 blister trays. Each blister tray contains one dual chamber syringe system, one needle and 2 alcohol swabs. It is available in the following strengths:

10 mcg	NDC 0009-5181-01
20 mcg	NDC 0009-5182-01

Caverject is also available as follows:

Caverject Sterile Powder (alprostadil for injection) packaged in vials, 6 vials per carton

10 mcg	NDC 0009-3778-05
20 mcg	NDC 0009-3701-05
40 mcg	NDC 0009-7686-04

Caverject Sterile Powder (alprostadil for injection) vials with diluent syringe, 6 syringe systems per carton

5 mcg	NDC 0009-7212-03
10 mcg	NDC 0009-3778-08
20 mcg	NDC 0009-3701-01

Caverject Injection ([alprostadil injection] aqueous), 5 ampoules per carton

10 mcg (10 mcg/mL)	NDC 0009-7655-02
20 mcg (20 mcg/mL)	NDC 0009-7654-02
40 mcg (40 mcg/2mL)	NDC 0009-7650-02

Rx only

Patient Instructions For

Caverject IMPULSE®

Dual Chamber System

alprostadil for injection

Read this information carefully before using Caverject [KAV-er-jeckt]. Read the information you get each time you renew your prescription, in case anything has changed. This is a summary and does not replace talking with your doctor when you start this medication and at check-ups. If you have any questions or concerns, talk to your doctor about them.

What is Caverject?

Caverject is a medicine to treat male impotence (erectile dysfunction). Caverject is injected into a specific area of the penis and should produce an erection in 5 to 20 minutes. The erection should last for no longer than 1 hour.

Caverject IMPULSE is for one use only and should be thrown away properly after a single use.

Caverject does not protect you from sexually transmitted diseases (STDs), such as HIV (the virus that causes AIDS). In addition, small amounts of bleeding at the injection site can increase the risk of passing diseases carried by the blood, such as HIV.

What are the causes of and treatments for impotence?

There are several causes of impotence. These include medications that you may be taking for other conditions, poor blood circulation in the penis, nerve damage, emotional problems, too much smoking or alcohol use, use of street drugs, and hormonal problems. Often, impotence is due to more than one cause.

Treatments for impotence include switching medications if you are taking a medication that causes impotence, prescription medications, medical devices that produce an erection, surgical procedures to correct blood flow in the penis, penile implants, and psychological counseling.

You should not stop taking any prescription medications, unless told to do so by your doctor.

The use of other medical treatments for impotence in combination with Caverject is not recommended. Discuss any concerns you may have about combination treatment with your doctor.

Who should not use Caverject?

Do not use Caverject if you have certain conditions that might cause long-lasting erections (lasting more than 4 hours). Long-lasting erections may cause penis damage. These conditions include:

sickle cell anemia or trait

leukemia

tumor of the bone marrow (multiple myeloma)

Do not use Caverject if you

have a penile implant

have an abnormally formed penis

have other penis problems

were told by your doctor not to have sex

Women and children should not use Caverject.

How should I use Caverject?

You will be treated with Caverject in your doctor's office to find out what dose is best for you. After that, you can inject it yourself at home. Do not use it more than 3 times a week. There should be at least 24 hours between doses. See your doctor for regular check-ups to be sure Caverject is not causing damage and that it is working as well as possible.

See the section "Instructions for Use" at the end of this leaflet for details about how to use Caverject.

What are the possible side effects of Caverject?

About 4 in 100 men who use Caverject may get erections that last more than 4 hours. These can cause serious and permanent damage. Call your doctor or seek professional help immediately if you still have an erection 4 hours after injection.

The most common side effect of Caverject is mild to moderate pain after injection. About one-third of patients report this effect.

You may get a small amount of bleeding at the injection site. This is more likely if you have a medical condition or are taking a medicine that interferes with blood clotting.

Call your doctor if you notice any redness, lumps, swelling, tenderness, or curving of the erect penis. Also, tell your doctor about any penis pain you did not have before or other penis problems you have.

There is a possibility of needle breakage with use of Caverject IMPULSE. To best avoid breaking the needle, you should pay careful attention to your doctor's instructions and try to handle the device properly. If the needle breaks during injection and you are able to see and grasp the broken end, you should remove it and contact your doctor. If you cannot see or cannot grasp the broken end, you should promptly contact your doctor.

How should I store Caverject IMPULSE?

Unmixed packages of Caverject IMPULSE should be stored at room temperature. Temperatures between 59° to 86°F (15° to 30°C) are allowed. Avoid storing Caverject IMPULSE at very high and very low temperatures.

During travel, do not let the medicine freeze or be stored at a temperature above 77°F (25°C). For example, do not store it in checked luggage during air travel or leave it in a closed automobile.

After mixing, Caverject IMPULSE should be used within 24 hours. It should be kept at a temperature of 77°F or below during this storage time.

General advice about prescription medicines

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have any concerns about Caverject, ask your doctor. Your doctor or pharmacist can give you information about Caverject that was written for health care professionals. Do not use Caverject for a condition for which it was not prescribed. Do not share Caverject with other people.

You can get more information about impotence (erectile dysfunction) and its treatment from the National Institutes of Health (Washington, DC), the American Foundation for Urological Diseases (Baltimore, MD), or the Impotence Institute of America (Washington, DC).

INSTRUCTIONS FOR USE

Before you use Caverject, your doctor must train you in how to prepare and give the injection properly.

Before using Caverject, talk to your doctor about what to expect when using it, possible side effects, and what to do if side effects occur. Your dose has been selected for your individual needs. Do not change your dose without consulting your doctor. If you are not sure of the volume or dose to be used, talk to your doctor or pharmacist.

Follow these instructions exactly to prepare and inject a sterile (germ-free) dose of Caverject.

Supplies Needed

Caverject IMPULSE is packaged with a needle for injection (Figure A) and alcohol swab.

Caverject IMPULSE is available in 10 and 20 mcg strengths.

MAKE SURE YOU HAVE THE RIGHT STRENGTH OF Caverject IMPULSE.

Prepare the Dose

Wash your hands thoroughly and dry them with a clean towel.

Remove the device, needle, and alcohol swabs from the blistered tray.

Using one of the alcohol swabs, clean the rubber membrane at the tip of the syringe (Figure B).

Peel the paper lid from the needle (Figure C).

Attach the needle to the device by pressing the

Wednesday, 29 August 2012

chlorpheniramine, pyrilamine, and phenylephrine

Generic Name: chlorpheniramine, pyrilamine, and phenylephrine (KLOR fe NEER a meen, pir IL a meen, FEN il EFF rin)

Brand names: AllerTan, Chlorex-A 12, Conal, MyHist-PD, Nalex A 12, Phena-Plus, Phena-S, Poly Hist PD, R-Tannate, Ru-Hist Forte, Tri-Hist Pediatric, Triotann-S Pediatric, Triple Tannate Pediatric, Triplex AD, ...show all 39 brand names.

What is chlorpheniramine, phenylephrine, and pyrilamine?

Chlorpheniramine and pyrilamine are antihistamines that reduce the effects of natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Phenylephrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of chlorpheniramine, phenylephrine, and pyrilamine is used to treat runny or stuffy nose, sneezing, itching, watery eyes, and sinus congestion caused by allergies, the common cold, or the flu.

Chlorpheniramine, phenylephrine, and pyrilamine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about chlorpheniramine, phenylephrine, and pyrilamine?

Do not use this medicine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects. Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Ask a doctor or pharmacist before using any other cold, cough, allergy, or pain medicine. Antihistamines and decongestants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine or decongestant. This medication may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly. Drinking alcohol can increase drowsiness caused by chlorpheniramine, phenylephrine, and pyrilamine. Before using chlorpheniramine, phenylephrine, and pyrilamine, tell your doctor if you regularly use other medicines that make you sleepy (such as sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by chlorpheniramine and pyrilamine.

What should I discuss with my healthcare provider before taking chlorpheniramine, phenylephrine, and pyrilamine?

severe or uncontrolled high blood pressure;

severe coronary artery disease;

diabetes;

overactive thyroid; or

asthma, pneumonia, or other breathing problems.

Ask a doctor or pharmacist if it is safe for you to take this medicine if you have:

liver disease;

kidney disease;

heart disease or high blood pressure;

glaucoma;

enlarged prostate;

bladder obstruction or other urination problems; or

a blockage in your digestive tract (stomach or intestines).

FDA pregnancy category C. It is not known whether chlorpheniramine, phenylephrine, and pyrilamine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Chlorpheniramine, phenylephrine, and pyrilamine can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using chlorpheniramine, phenylephrine, and pyrilamine.

How should I take chlorpheniramine, phenylephrine, and pyrilamine?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Cough or cold medicine is usually taken only for a short time until your symptoms clear up.

Do not give this medication to a child younger than 4 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Do not crush, chew, or break an extended-release tablet. Swallow the pill whole. Breaking or crushing the pill may cause too much of the drug to be released at one time.

Measure liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Shake the oral suspension (liquid) well just before you measure a dose. Store at room temperature away from moisture, heat, and light.

See also: Chlorpheniramine, pyrilamine, and phenylephrine dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include dry mouth, dilated pupils, nausea, vomiting, and warmth, redness, or tingly feeling under your skin.

What should I avoid while taking chlorpheniramine, phenylephrine, and pyrilamine?

Ask a doctor or pharmacist before using any other cold, cough, allergy, or pain medicine. Antihistamines and decongestants are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine or decongestant. This medication may cause blurred vision and may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly. Drinking alcohol can increase certain side effects of this medication.

Avoid taking this medication if you also take diet pills, caffeine pills, or other stimulants (such as ADHD medications). Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.

Chlorpheniramine, phenylephrine, and pyrilamine side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as:

severe dizziness, anxiety, restless feeling, or nervousness;

fast, pounding, or uneven heartbeats;

confusion, hallucinations, unusual thoughts or behavior;

feeling like you might pass out;

urinating less than usual or not at all;

easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms;

increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure); or

nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Less serious side effects may include:

upset stomach, constipation;

dry mouth;

blurred vision;

dizziness, drowsiness;

problems with memory;

sleep problems (insomnia); or

feeling restless or excited (especially in children).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Chlorpheniramine, pyrilamine, and phenylephrine Dosing Information

Usual Adult Dose for Allergic Rhinitis:

Chlorpheniramine/phenylephrine/pyrilamine 2 mg-7.5 mg-12.5 mg/5 mL:
5 to 10 mL orally every 4 to 6 hours not to exceed 60 mg of phenylephrine in 24 hours.

Chlorpheniramine/phenylephrine/pyrilamine 4 mg-10 mg-25 mg oral tablet, extended release:
1 tablet orally 2 to 3 times daily.

Chlorpheniramine/phenylephrine/pyrilamine 8 mg-12.5 mg-15 mg/5 mL:
5 to 10 mL orally every 12 hours not to exceed 20 mL in 24 hours.

Chlorpheniramine/phenylephrine/pyrilamine 2 mg-10 mg-10 mg oral tablet:
1 to 2 tablets orally every 4 to 6 hours.

Usual Adult Dose for Cold Symptoms:

Usual Pediatric Dose for Allergic Rhinitis:

Chlorpheniramine/phenylephrine/pyrilamine 2 mg-5 mg-12.5 mg/5 mL:
2 years to 6 years: 2.5 to 5 mL orally every 12 hours as needed.
6 years or older: 5 to 10 mL orally every 12 hours as needed.

Chlorpheniramine/phenylephrine/pyrilamine 2 mg-7.5 mg-12.5 mg/5 mL:
2 yrs to 5 yrs: 2.5 mL orally every 4 to 6 hours not to exceed 15 mg of phenylephrine in 24 hours.
6 yrs to 11 yrs: 5 mL orally every 4 to 6 hours not to exceed 30 mg of phenylephrine in 24 hours.
12 years or older: 5 to 10 mL orally every 4 to 6 hours not to exceed 60 mg of phenylephrine in 24 hours.

Chlorpheniramine/phenylephrine/pyrilamine 4 mg-10 mg-25 mg oral tablet, extended release:
6 yrs to 11 yrs: 1/2 tablet orally 2 to 3 times daily.
12 years or older: 1 tablet orally 2 to 3 times daily.

Chlorpheniramine/phenylephrine/pyrilamine 8 mg-12.5 mg-15 mg/5 mL:
2 yrs to 5 yrs: 2.5 mL orally every 12 hours not to exceed 5 mL in 24 hours.
6 yrs to 12 yrs: 5 mL orally every 12 hours not to exceed 10 mL 24 hours.
12 years or older: 5 to 10 mL orally every 12 hours not to exceed 20 mL in 24 hours.

Chlorpheniramine/phenylephrine/pyrilamine 2 mg-10 mg-10 mg oral tablet:
6 yrs to 12 yrs: 1 tablet orally every 4 to 6 hours.
12 years or older: 1 to 2 tablets orally every 4 to 6 hours.

Usual Pediatric Dose for Cold Symptoms:

What other drugs will affect chlorpheniramine, phenylephrine, and pyrilamine?

Cold or allergy medicine, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by chlorpheniramine or pyrilamine. Tell your doctor if you regularly use any of these medicines, or any other cough and cold medications.

Tell your doctor about all other medications you use, especially:

digoxin (Lanoxin);

blood pressure medication;

an antidepressant;

a barbiturate such as phenobarbital (Solfoton) and others;

a diuretic (water pill);

medication to treat irritable bowel syndrome;

bladder or urinary medications such as oxybutynin (Ditropan, Oxytrol) or tolterodine (Detrol);

aspirin or salicylates (such as Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others); or

a beta-blocker such as atenolol (Tenormin), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), and others.

This list is not complete and there may be other drugs that can interact with chlorpheniramine, phenylephrine, and pyrilamine. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More chlorpheniramine, pyrilamine, and phenylephrine resources

Chlorpheniramine, pyrilamine, and phenylephrine Side Effects (in more detail)
Chlorpheniramine, pyrilamine, and phenylephrine Dosage
Chlorpheniramine, pyrilamine, and phenylephrine Use in Pregnancy & Breastfeeding
Drug Images
Chlorpheniramine, pyrilamine, and phenylephrine Drug Interactions
Chlorpheniramine, pyrilamine, and phenylephrine Support Group
0 Reviews for Chlorpheniramine, pyrilamine, and phenylephrine - Add your own review/rating

Compare chlorpheniramine, pyrilamine, and phenylephrine with other medications

Cold Symptoms
Hay Fever

Where can I get more information?

Your pharmacist can provide more information about chlorpheniramine, phenylephrine, and pyrilamine.

See also: chlorpheniramine, pyrilamine, and phenylephrine side effects (in more detail)

Saturday, 25 August 2012

VEGF/VEGFR inhibitors

A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Vascular endothelial growth factor (VEGF)/ vascular endothelial growth factor receptor (VEGFR) inhibitors are agents that inhibit the activity of VEGF and VEGFR. VEGR and VEGFR (a tyrosine kinase receptor) signaling modulates angiogenesis, which involves making of new blood vessels from existing blood vessels.

Abnormal angiogenesis is known to occur in cancer, degenerative eye conditions and other conditions that involve inflammation. Specific monoclonal antibodies can be used as VEGF inhibitors and particular tyrosine kinase inhibitors are used as VEGFR inhibitors.

Vascular endothelial growth factor (VEGF)/ vascular endothelial growth factor receptor (VEGFR) inhibitors are used to treat various types of cancers.

Thursday, 23 August 2012

Cecon Solution

Pronunciation: ASS-kor-bik ASS-id
Generic Name: Ascorbic Acid
Brand Name: Cecon and Protexin

Cecon Solution is used for:

Treating and preventing low levels of vitamin C. It may also be used for other conditions as determined by your doctor.

Cecon Solution is a vitamin. It works by supplementing vitamin C, which is used in many functions in the body.

Do NOT use Cecon Solution if:

you are allergic to any ingredient in Cecon Solution

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

Before using Cecon Solution:

Some medical conditions may interact with Cecon Solution. 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 diabetes, glucose-6-phosphate dehydrogenase deficiency, a high iron level in the blood, anemia (eg, sickle cell, sideroblastic, thalassemia), or kidney stones

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

Anticoagulants (eg, warfarin) because side effects may be increased by Cecon Solution

This may not be a complete list of all interactions that may occur. Ask your health care provider if Cecon Solution 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 Cecon Solution:

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

Cecon Solution may be taken with or without food.

You may drop the dose of Cecon Solution directly into your mouth or mix it with cereal, milk, or water.

Take Cecon Solution with a full glass of water (8 oz/240 mL). Do not lie down for 30 minutes after taking Cecon Solution.

Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.

If you miss a dose of Cecon Solution, 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 Cecon Solution.

Important safety information:

Do not take large doses of vitamins (megadoses or megavitamin therapy) while taking Cecon Solution unless directed to by your doctor.

Cecon Solution may cause incorrect results with some in-home cholesterol test kits. Check with your doctor or pharmacist if you are taking Cecon Solution and need to check your cholesterol at home.

Diabetes patients - Cecon Solution may cause incorrect test results with some urine glucose tests. Check with your doctor before you adjust the dose of your diabetes medicine or change your diet.

Cecon Solution may cause incorrect test results with kits used to check for blood in the stool. Check with your doctor if you are taking Cecon Solution when using the test kit.

PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Cecon Solution, discuss with your doctor the benefits and risks of using Cecon Solution during pregnancy. Cecon Solution is excreted in breast milk. If you are or will be breast-feeding while you are using Cecon Solution, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Cecon Solution:

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; nausea; upset stomach; vomiting.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); kidney stones (eg, abdominal pain/back pain, painful urination).

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: Cecon 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 gout.

Proper storage of Cecon Solution:

Store Cecon Solution at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Cecon Solution out of the reach of children and away from pets.

General information:

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

Cecon Solution 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 Cecon Solution. 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

More Cecon resources

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

Compare Cecon with other medications

Dietary Supplementation
Scurvy
Urinary Acidification

Tuesday, 21 August 2012

Citalopram Oral Solution

Dosage Form: oral solution
Citalopram Hydrobromide Oral Solution

Warning

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of citalopram hydrobromide or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Citalopram Hydrobromide Oral Solution is not approved for use in pediatric patients. (See WARNINGS, Clinical Worsening and Suicide Risk, PRECAUTIONS, Information for Patients, and PRECAUTIONS, Pediatric Use.)

Citalopram Oral Solution Description

Citalopram HBr is an orally administered selective serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that of other SSRI's or of tricyclic, tetracyclic, or other available antidepressant agents. Citalopram HBr is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-flurophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, HBr with the following structural formula:

The molecular formula is C20H22BrFN2O and its molecular weight is 405.35.

Citalopram HBr occurs as a fine, white to off-white powder. Citalopram HBr is sparingly soluble in water and soluble in ethanol.

Citalopram hydrobromide is available as an oral solution.

Citalopram hydrobromide oral solution contains citalopram HBr equivalent to 2 mg/mL citalopram base. It also contains the following inactive ingredients: Sorbitol, Purified Water, Propylene Glycol, Methylparaben, Peppermint Flavor, and Propylparaben.

Citalopram Oral Solution - Clinical Pharmacology

Pharmacodynamics

The mechanism of action of citalopram HBr as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14-day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer.

Citalopram has no or very low affinity for 5-HT1A, 5-HT2A, dopamine D1 and D2, α1-, α2-, and β-adrenergic, histamine H1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs.

Pharmacokinetics

The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10-60 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose. The tablet and oral solution dosage forms of citalopram HBr are bioequivalent.

Absorption and Distribution

Following a single 40 mg oral dose of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. The volume of distribution of citalopram is about 12 L/kg and the binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%.

Metabolism and Elimination

Following intravenous administrations of citalopram, the fraction of drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance.

Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In humans, unchanged citalopram is the predominant compound in plasma. At steady state, the concentrations of citalopram's metabolites, DCT and DDCT, in plasma are approximately one-half and one- tenth, respectively, that of the parent drug. In vitro studies show that citalopram is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of citalopram.

In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of citalopram.

Population Subgroups

Age – Citalopram pharmacokinetics in subjects ≥ 60 years of age were compared to younger subjects in two normal volunteer studies. In a single dose study, citalopram AUC and half-life were increased in the elderly subjects by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively. 20 mg is the recommended dose for most elderly patients (see DOSAGE AND ADMINISTRATION).

Gender - In three pharmacokinetic studies (total N=32), citalopram AUC in women was one and a half to two times that in men. This difference was not observed in five other pharmacokinetic studies (total N=114). In clinical studies, no differences in steady state serum citalopram levels were seen between men (N=237) and women (N=388). There were no gender differences in the pharmacokinetics of DCT and DDCT. No adjustment of dosage on the basis of gender is recommended.

Reduced hepatic function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 20 mg is the recommended dose for most hepatically impaired patients (see DOSAGE AND ADMINISTRATION).

Reduced renal function - In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of citalopram in patients with severely reduced renal function (creatinine clearance < 20 mL/min).

Drug-Drug Interactions

In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. However, in vivo data to address this question are limited.

Since CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of 3A4 (e.g., ketoconazole, itraconazole, and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g., omeprazole) might decrease the clearance of citalopram. However, coadministration of citalopram and the potent 3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance. Citalopram steady state levels were not significantly different in poor metabolizers and extensive 2D6 metabolizers after multiple-dose administration of citalopram hydrobromide, suggesting that coadministration, with citalopram hydrobromide, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on citalopram metabolism. See Drug Interactions under PRECAUTIONS for more detailed information on available drug interaction data.

Clinical Efficacy Trials

The efficacy of citalopram hydrobromide as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18-66) meeting DSM-III or DSM-III-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed citalopram hydrobromide doses of 10, 20, 40, and 60 mg/day, showed that citalopram hydrobromide at doses of 40 and 60 mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram hydrobromide showed significantly greater improvement than placebo patients on the HAMD total score, HAMD item 1, and the CGI Severity score. In three additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram hydrobromide and patients receiving placebo was not statistically significant, possibly due to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose.

In two long-term studies, depressed patients who had responded to citalopram hydrobromide during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40 mg/day in one study and flexible doses of 20-60 mg/day in the second study) were randomized to continuation of citalopram hydrobromide or to placebo. In both studies, patients receiving continued citalopram hydrobromide treatment experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed-dose study, the decreased rate of depression relapse was similar in patients receiving 20 or 40 mg/day of citalopram hydrobromide.

Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.

Comparison of Clinical Trial Results Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated.

Indications and Usage for Citalopram Oral Solution

Citalopram hydrobromide is indicated for the treatment of depression.

The efficacy of citalopram hydrobromide in the treatment of depression was established in 4-6 week, controlled trials of outpatients whose diagnosis corresponded most closely to the DSM- III and DSM-III-R category of major depressive disorder (see CLINICAL PHARMACOLOGY).

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.

The antidepressant action of citalopram hydrobromide in hospitalized depressed patients has not been adequately studied.

The efficacy of citalopram hydrobromide in maintaining an antidepressant response for up to 24 weeks following 6 to 8 weeks of acute treatment was demonstrated in two placebo-controlled trials (see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use citalopram hydrobromide for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Contraindications

Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS).

Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).

Citalopram hydrobromide is contraindicated in patients with a hypersensitivity to citalopram or any of the inactive ingredients in Citalopram Hydrobromide Oral Solution.

Warnings

WARNINGS-Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1
Age Range	Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
	Increases Compared to Placebo
<18	14 additional cases
18-24	5 additional cases
	Decreases Compared to Placebo
25-64	1 fewer case
≥65	6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION – Discontinuation of treatment with citalopram hydrobromide, for a description of the risks of discontinuation of citalopram hydrobromide).

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Citalopram Hydrobromide Oral Solution should be written for the smallest quantity of liquid consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Citalopram Hydrobromide Oral Solution is not approved for use in treating bipolar depression.

Potential for Interaction with Monoamine Oxidase Inhibitors

In patients receiving serotonin reuptake inhibitor drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on a MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combined use of SSRIs and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that citalopram hydrobromide should not be used in combination with a MAOI, or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 14 days should be allowed after stopping citalopram hydrobromide before starting a MAOI.

Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions

The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including citalopram treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

The concomitant use of citalopram with MAOIs intended to treat depression is contraindicated. If concomitant treatment of citalopram with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

The concomitant use of citalopram with serotonin precursors (such as tryptophan) is not recommended. Treatment with citalopram and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Precautions

General

Discontinuation of Treatment with Citalopram

During marketing of Citalopram and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with Citalopram. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).

Abnormal Bleeding

SSRIs and SNRIs, including Citalopram, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of Citalopram and NSAIDs, aspirin, or other drugs that affect coagulation.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including citalopram. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of citalopram should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and /or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Activation of Mania/Hypomania

In placebo-controlled trials of citalopram hydrobromide , some of which included patients with bipolar disorder, activation of mania/hypomania was reported in 0.2% of 1063 patients treated with citalopram hydrobromide and in none of the 446 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with other marketed antidepressants. As with all antidepressants, citalopram hydrobromide should be used cautiously in patients with a history of mania.

Seizures

Although anticonvulsant effects of citalopram have been observed in animal studies, citalopram hydrobromide has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of citalopram hydrobromide , seizures occurred in 0.3% of patients treated with citalopram hydrobromide (a rate of one patient per 98 years of exposure) and 0.5% of patients treated with placebo (a rate of one patient per 50 years of exposure). Like other antidepressants, citalopram hydrobromide should be introduced with care in patients with a history of seizure disorder.

Interference with Cognitive and Motor Performance

In studies in normal volunteers, citalopram hydrobromide in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram hydrobromide therapy does not affect their ability to engage in such activities.

Use in Patients with Concomitant Illness

Clinical experience with citalopram hydrobromide in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using citalopram hydrobromide in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.

Citalopram hydrobromide has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing. However, the electrocardiograms of 1116 patients who received citalopram hydrobromide in clinical trials were evaluated and the data indicate that citalopram hydrobromide is not associated with the development of clinically significant ECG abnormalities.

In subjects with hepatic impairment, citalopram clearance was decreased and plasma concentrations were increased. The use of citalopram hydrobromide in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see DOSAGE AND ADMINISTRATION).

Because citalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with citalopram hydrobromide, however, it should be used with caution in such patients (see DOSAGE AND ADMINISTRATION).

Information for Patients

Physicians are advised to discuss the following issues with patients for whom they prescribe Citalopram.

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Citalopram Hydrobromide and triptans, tramadol or other serotonergic agents.

Although in controlled studies Citalopram has not been shown to impair psychomotor performance, any psychoactive drug may impair judgment, thinking, or motor skills, so patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Citalopram therapy does not affect their ability to engage in such activities.

Patients should be told that, although Citalopram has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of Citalopram and alcohol in depressed patients is not advised.

Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.

Patients should be cautioned about the concomitant use of Citalopram and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be advised to notify their physician if they are breastfeeding an infant.

While patients may notice improvement with Citalopram Hydrobromide therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Citalopram Hydrobromide Oral Solution and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Citalopram Hydrobromide Oral Solution. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Citalopram Hydrobromide Oral Solution.

Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Laboratory Tests

There are no specific laboratory tests recommended.

Drug Interactions

Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs including citalopram hydrobromide, and the potential for serotonin syndrome, caution is advised when citalopram hydrobromide is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see WARNINGS-Serotonin Syndrome). The concomitant use of Citalopram Hydrobromide with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS – Drug Interactions).

Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of citalopram hydrobromide with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS-Serotonin Syndrome).

CNS Drugs - Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs.

Alcohol - Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking citalopram hydrobromide is not recommended.

Monoamine Oxidase Inhibitors (MAOIs) -See CONTRAINDICATIONS AND WARNINGS.

Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Citalopram is initiated or discontinued.

Cimetidine - In subjects who had received 21 days of 40 mg/day citalopram hydrobromide, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The clinical significance of these findings is unknown.

Digoxin - In subjects who had received 21 days of 40 mg/day citalopram hydrobromide, combined administration of Citalopram Hydrobromide and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.

Lithium - Coadministration of citalopram hydrobromide (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when citalopram hydrobromide and lithium are coadministered.

Pimozide - In a controlled study, a single dose of pimozide 2 mg co-administered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.

Theophylline - Combined administration of citalopram hydrobromide (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.

Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is clinically warranted, appropriate. observation of the patient is advised.

Warfarin - Administration of 40 mg/day citalopram hydrobromide for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.

Carbamazepine - Combined administration of citalopram hydrobromide (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered.

Triazolam - Combined administration of citalopram hydrobromide (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.

Ketoconazole - Combined administration of citalopram hydrobromide (40 mg) and ketoconazole (200 mg) decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.

CYP3A4 and 2C19 inhibitors - In vitro studies indicated that CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram. However, coadministration of citalopram (40 mg) and ketoconazole (200 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance.

Metoprolol - Administration of 40 mg/day citalopram hydrobromide for 22 days resulted in a two-fold increase in the plasma levels of the beta-adrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of citalopram hydrobromide and metoprolol had no clinically significant effects on blood pressure or heart rate.

Imipramine and Other Tricyclic Antidepressants (TCAs) - In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of citalopram hydrobromide (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with citalopram hydrobromide.

Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and citalopram hydrobromide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which is equivalent to 20 times the maximum recommended human daily dose (MRHD) of 60 mg on a surface area (mg/m2) basis. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day, doses which are approximately 1.3 and 4 times the MRHD, respectively, on a mg/m2 basis. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.

Mutagenesis

Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/ in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.

Impairment of Fertility

When citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses ≥32 mg/kg/day, approximately 5 times the maximum recommended human dose (MRHD) of 60 mg/day on a body surface area (mg/m2) basis. Gestation duration was increased at 48 mg/kg/day, approximately 8 times the MRHD.

Pregnancy

Pregnancy Category C

In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses.

In two rat embryo/fetal development studies, oral administration of citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times MRHD of 60 mg/day on a body surface area (mg/m2) basis. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental, no-effect dose of 56 mg/kg/day is approximately 9 times the MRHD on mg/m2 basis. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/m2 basis. Thus, teratogenic effects were observed at a maternally toxic dose in the rat and were not observed in the rabbit.

When female rats were treated with citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the MRHD on a mg/m2 basis. The no-effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m2 basis. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥24 mg/kg/day, approximately 4 times the MRHD on a mg/m2 basis. A no-effect dose was not determined in that study.

There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy-Nonteratogenic Effects

Neonates exposed to Citalopram Hydrobromide and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS).

Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective, case-control study of 377 women whose infants were born healthy, the risk of developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.

When treating a pregnant woman with Citalopram Hydrobromide during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physician should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

Labor and Delivery

The effect of citalopram hydrobromide on labor and delivery in humans is unknown.

Nursing Mothers

As has been found to occur with many other drugs, citalopram is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breast feeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother and in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or citalopram hydrobromide therapy should take into account the risks of citalopram exposure for the infant and the benefits of citalopram hydrobromide treatment for the mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS – Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with Citalopram, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Citalopram Hydrobromide Oral Solution in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use

Of 4422 patients in clinical studies of citalopram hydrobromide, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Most elderly patients treated with citalopram hydrobromide in clinical trials received daily doses between 20 and 40 mg (see DOSAGE AND ADMINISTRATION).

SSRIs and SNRIs, including citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS,

Friday, 31 August 2012

Caverject

Caverject Description

Caverject - Clinical Pharmacology

Pharmacokinetics

Pharmacokinetics in Special Populations

Drug-Drug Interactions

Clinical Studies

INDICATION AND USAGE

Contraindications

Warnings

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General Precautions

Information for the Patient

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Pregnancy, Nursing Mothers, and Pediatric Use

Geriatric Use

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Penile Pain

Prolonged Erection/Priapism

Hematoma/Ecchymosis

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Caverject Dosage and Administration

Initial Titration in Physician's Office

Maintenance Therapy

Caverject as an Adjunct to the Diagnosis of Erectile Dysfunction

General Procedure for Solution Preparation

How is Caverject Supplied

Patient Instructions ForCaverject IMPULSE®Dual Chamber Systemalprostadil for injection

Wednesday, 29 August 2012

chlorpheniramine, pyrilamine, and phenylephrine

What is chlorpheniramine, phenylephrine, and pyrilamine?

What is the most important information I should know about chlorpheniramine, phenylephrine, and pyrilamine?

What should I discuss with my healthcare provider before taking chlorpheniramine, phenylephrine, and pyrilamine?

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What happens if I miss a dose?

What happens if I overdose?

What should I avoid while taking chlorpheniramine, phenylephrine, and pyrilamine?

Chlorpheniramine, phenylephrine, and pyrilamine side effects

Chlorpheniramine, pyrilamine, and phenylephrine Dosing Information

What other drugs will affect chlorpheniramine, phenylephrine, and pyrilamine?

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Saturday, 25 August 2012

VEGF/VEGFR inhibitors

See also

Drug List:

Thursday, 23 August 2012

Cecon Solution

Cecon Solution is used for:

Do NOT use Cecon Solution if:

Before using Cecon Solution:

How to use Cecon Solution:

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If OVERDOSE is suspected:

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Tuesday, 21 August 2012

Citalopram Oral Solution

Citalopram Oral Solution Description

Citalopram Oral Solution - Clinical Pharmacology

Pharmacodynamics

Pharmacokinetics

Indications and Usage for Citalopram Oral Solution

Contraindications

Warnings

Precautions

Information for Patients

Laboratory Tests

Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

Labor and Delivery

Nursing Mothers

Pediatric Use

Patient Instructions For

Caverject IMPULSE®

Dual Chamber System

alprostadil for injection