Ulfamid

Ulfamid injection, supplied as a concentrated solution for intravenous injection, is intended for intravenous use only. Ulfamid injection is indicated in some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or as an alternative to the oral dosage forms for short term use in patients who are unable to take oral medication for the following conditions:

1. Short term treatment of active duodenal ulcer. Most adult patients heal within 4 weeks; there is rarely reason to use Ulfamid at full dosage for longer than 6 to 8weeks. Studies have not assessed the safety of Ulfamid in uncomplicated active duodenal ulcer for periods of more than 8 weeks.
2. Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer. Controlled studies in adults have not extended beyond one year.
3. Short term treatment of active benign gastric ulcer. Most adult patients heal within 6 weeks. Studies have not assessed the safety or efficacy of Ulfamid in uncomplicated active benign gastric ulcer for periods of more than 8 weeks.
4. Short term treatment of gastroesophageal reflux disease (GERD). Ulfamid is indicated for short term treatment of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
   Ulfamid is also indicated for the short term treatment of esophagitis due to GERD including erosive or ulcerative disease diagnosed by endoscopy (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).
5. Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies).

In some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients who are unable to take oral medication, Ulfamid injection may be administered until oral therapy can be instituted.

The recommended dosage for Ulfamid injection in adult patients is 20 mg intravenously q 12 h.

The doses and regimen for parenteral administration in patients with GERD have not been established.

Dosage for Pediatric Patients

See PRECAUTIONS, Pediatric Use.

The studies described in PRECAUTIONS, Pediatric Use suggest that the starting dose in pediatric patients 1-16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15 minute infusion) q 12 h up to 40 mg/day.

While published uncontrolled clinical studies suggest effectiveness of Ulfamid in the treatment of peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or gastric pH determination and endoscopy. Published uncontrolled studies in pediatric patients have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.

No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1year of age.

Dosage Adjustments for Patients with Moderate or Severe Renal Insufficiency

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

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

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

The dosage of Ulfamid in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult intravenous dose is 20mg q 12 h. Doses should be adjusted to individual patient needs and should continue as long as clinically indicated. In some patients, a higher starting dose may be required. Oral doses up to 160 mg q 6 h have been administered to some adult patients with severe Zollinger-Ellison Syndrome.

Preparation of Intravenous Solutions

To prepare Ulfamid intravenous solutions, aseptically dilute 2 mL of Ulfamid injection (solution containing 10 mg/mL) with 0.9% Sodium Chloride Injection or other compatible intravenous solution (see Stability), to a total volume of either 5 mL or 10 mL and inject over a period of not less than 2 minutes.

To prepare Ulfamid intravenous infusion solutions, aseptically dilute 2 mL of Ulfamid injection with 100 mL of 5% dextrose or other compatible solution (see Stability), and infuse over a 15 to 30 minute period.

Concomitant Use of Antacids

Antacids may be given concomitantly if needed.

Stability

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

When added to or diluted with most commonly used intravenous solutions, e.g., Water for Injection, 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, or Lactated Ringer's Injection, diluted Ulfamid injection is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature – see HOW SUPPLIED, Storage.

When added to or diluted with Sodium Bicarbonate Injection, 5%, Ulfamid injection at a concentration of 0.2 mg/mL (the recommended concentration of Ulfamid intravenous infusion solutions) is physically and chemically stable (i.e., maintains at least 90% of initialpotency) for 7 days at room temperature – see HOW SUPPLIED, Storage. However, a precipitate may form at higher concentrations of Ulfamid injection ( > 0.2mg/mL) in Sodium Bicarbonate Injection, 5%.

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

WARNINGS

No information provided.

PRECAUTIONS

General

Symptomatic response to therapy with famo-tidine injection does not preclude the presence of gastric malignancy.

Patients with Moderate or Severe Renal Insufficiency

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

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

Pregnancy

Pregnancy Category B

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

Nursing Mothers

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

Pediatric Use

Use of Ulfamid in pediatric patients 1-16 years of age is supported by evidence from adequate and well-controlled studies of famoti-dine in adults, and by thefollowing studies in pediatric patients: In published studies in small numbers of pediatric patients 1-15 years of age, clearance of Ulfamid was similar to that seen in adults. In pediatric patients 11-15 years of age, oral dosesof 0.5 mg/kg were associated with a mean area under the curve (AUC) similar to that seen in adults treated orally with 40 mg. Similarly, in pediatric patients 1-15 years of age, intravenous doses of 0.5 mg/kg were associated with a mean AUC similar to that seen in adults treated intravenously with 40 mg. Limited published studies also suggest that the relationship between serum concentration and acid suppression is similar in pediatric patients 1-15 years of age as compared with adults. These studies suggest that the starting dose for pediatric patients 1-16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15 minute infusion) q 12 h up to 40 mg/day.

While published uncontrolled clinical studies suggest effectiveness of Ulfamid in the treatment of peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy. Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or gastric pH determination and endoscopy. Published uncontrolled studies in pediatric patients have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.

No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1year of age.

Geriatric Use

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

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

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

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

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

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

Body as a Whole: fever, asthenia, fatigue

Cardiovascular: arrhythmia, AV block, palpitation

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

Hematologic: rare cases of agranulocyto-sis, pancytopenia, leukopenia, thrombocy-topenia

Hypersensitivity: anaphylaxis, angioedema, orbital or facial edema, urticaria, rash, conjuc-tival injection

Musculoskeletal: musculoskeletal pain including muscle cramps, arthralgia

Nervous System/Psychiatric: grand mal seizure; psychic disturbances, which were reversible in cases for which follow-up was obtained, including hallucinations, confusion, agitation, depression, anxiety, decreased libido; paresthesia; insomnia; somnolence

Respiratory: bronchospasm

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

Special Senses: tinnitus, taste disorder

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

The adverse reactions reported for Ulfamid tablets may also occur with Ulfamid for oral suspension, Ulfamid orally disintegrating tablets, Ulfamid injection preservative free in plastic container or Ulfamid injection.

There is no experience to date with deliberate overdosage. Oral doses of up to 640 mg/day have been given to adult patients with pathological hypersecretory conditions with no serious adverse effects. In the event of overdosage, treatment should be symptomatic and supportive. Unabsorbed material should be removed from the gastrointestinal tract, the patient should be monitored, and supportive therapy should be employed.

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

Orally administered Ulfamid is incompletely absorbed and its bioavailability is 40 to 45%. Ulfamid undergoes minimal first-pass metabolism. After oral doses, peak plasma levels occur in 1to 3 hours. Plasma levels after multiple doses are similar to those after single doses. Fifteen to 20% of Ulfamid in plasma is protein bound. Ulfamid has an elimination half-life of 2.5 to 3.5 hours. Ulfamid is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/min, indicating some tubular excretion. Twenty-five to 30% of an oral dose and 65 to 70% of an intravenous dose are recovered in the urine as unchanged compound. The only metabolite identified in man is the S-oxide.

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

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

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain