Naltrexone Hydrochloride (Page 4 of 6)

Pregnancy

Teratogenic Effects

Category C

Naltrexone has been shown to increase the incidence of early fetal loss when given to rats at doses ≥30 mg/kg/day (180 mg/m 2 /day; 5 times the recommended therapeutic dose, based on body surface area) and to rabbits at oral doses ≥60 mg/kg/day (720 mg/m 2 /day; 18 times the recommended therapeutic dose, based on body surface area). There was no evidence of teratogenicity when naltrexone was administered orally to rats and rabbits during the period of major organogenesis at doses up to 200 mg/kg/day (32 and 65 times the recommended therapeutic dose, respectively, based on body surface area).

Rats do not form appreciable quantities of the major human metabolite, 6-β-naltrexol; therefore, the potential reproductive toxicity of the metabolites in rats is not known.

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

Labor and Delivery

Whether or not naltrexone hydrochloride affects the duration of labor and delivery is unknown.

Nursing Mothers

In animal studies, naltrexone and 6-β-naltrexol were excreted in the milk of lactating rats dosed orally with naltrexone.

Whether or not naltrexone hydrochloride is excreted in human milk is unknown. Because many drugs are excreted in human milk, caution should be exercised when naltrexone is administered to a nursing woman.

Pediatric Use

The safe use of naltrexone hydrochloride in pediatric patients younger than 18 years old has not been established.

ADVERSE REACTIONS

During two randomized, double-blind placebo-controlled 12-week trials to evaluate the efficacy of naltrexone hydrochloride as an adjunctive treatment of alcohol dependence, most patients tolerated naltrexone hydrochloride well. In these studies, a total of 93 patients received naltrexone hydrochloride at a dose of 50 mg once daily. Five of these patients discontinued naltrexone hydrochloride because of nausea. No serious adverse events were reported during these two trials.

While extensive clinical studies evaluating the use of naltrexone hydrochloride in detoxified, formerly opioid-dependent individuals failed to identify any single, serious untoward risk of naltrexone hydrochloride use, placebo-controlled studies employing up to five fold higher doses of naltrexone hydrochloride (up to 300 mg per day) than that recommended for use in opiate receptor blockade have shown that naltrexone hydrochloride causes hepatocellular injury in a substantial proportion of patients exposed at higher doses (see WARNINGS and PRECAUTIONS, Laboratory Tests).

Aside from this finding, and the risk of precipitated opioid withdrawal, available evidence does not incriminate naltrexone hydrochloride, used at any dose, as a cause of any other serious adverse reaction for the patient who is “opioid-free.” It is critical to recognize that naltrexone hydrochloride can precipitate or exacerbate abstinence signs and symptoms in any individual who is not completely free of exogenous opioids.

Patients with addictive disorders, especially opioid addiction, are at risk for multiple numerous adverse events and abnormal laboratory findings, including liver function abnormalities. Data from both controlled and observational studies suggest that these abnormalities, other than the dose-related hepatotoxicity described above, are not related to the use of naltrexone hydrochloride.

Among opioid-free individuals, naltrexone hydrochloride administration at the recommended dose has not been associated with a predictable profile of serious adverse or untoward events. However, as mentioned above, among individuals using opioids, naltrexone hydrochloride may cause serious withdrawal reactions (see CONTRAINDICATIONS, WARNINGS, DOSAGE AND ADMINISTRATION).

Reported Adverse Events

Naltrexone hydrochloride has not been shown to cause significant increases in complaints in placebo-controlled trials in patients known to be free of opioids for more than 7 to 10 days. Studies in alcoholic populations and in volunteers in clinical pharmacology studies have suggested that a small fraction of patients may experience an opioid withdrawal-like symptom complex consisting of tearfulness, mild nausea, abdominal cramps, restlessness, bone or joint pain, myalgia, and nasal symptoms. This may represent the unmasking of occult opioid use, or it may represent symptoms attributable to naltrexone. A number of alternative dosing patterns have been recommended to try to reduce the frequency of these complaints.

Alcoholism

In an open label safety study with approximately 570 individuals with alcoholism receiving naltrexone hydrochloride, the following new-onset adverse reactions occurred in 2% or more of the patients: nausea (10%), headache (7%), dizziness (4%), nervousness (4%), fatigue (4%), insomnia (3%), vomiting (3%), anxiety (2%) and somnolence (2%).

Depression, suicidal ideation, and suicidal attempts have been reported in all groups when comparing naltrexone, placebo, or controls undergoing treatment for alcoholism.

RATE RANGES OF NEW ONSET EVENTS
Naltrexone Placebo
Depression 0 to 15% 0 to 17%
Suicide Attempt/Ideation 0 to 1% 0 to 3%

Although no causal relationship with naltrexone hydrochloride is suspected, physicians should be aware that treatment with naltrexone does not reduce the risk of suicide in these patients (see PRECAUTIONS).

Opioid Addiction

The following adverse reactions have been reported both at baseline and during the naltrexone hydrochloride clinical trials in opioid addiction at an incidence rate of more than 10%:

Difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy, joint and muscle pain, and headache.

The incidence was less than 10% for:

Loss of appetite, diarrhea, constipation, increased thirst, increased energy, feeling down, irritability, dizziness, skin rash, delayed ejaculation, decreased potency, and chills.

The following events occurred in less than 1% of subjects:

Respiratory
Nasal congestion, itching, rhinorrhea, sneezing, sore throat, excess mucus or phlegm, sinus trouble, heavy breathing, hoarseness, cough, shortness of breath.

Cardiovascular
Nose bleeds, phlebitis, edema, increased blood pressure, non-specific ECG changes, palpitations, tachycardia.

Gastrointestinal
Excessive gas, hemorrhoids, diarrhea, ulcer.

Musculoskeletal
Painful shoulders, legs or knees; tremors, twitching.

Genitourinary
Increased frequency of, or discomfort during, urination; increased or decreased sexual interest.

Dermatologic
Oily skin, pruritus, acne, athlete’s foot, cold sores, alopecia.

Psychiatric
Depression, paranoia, fatigue, restlessness, confusion, disorientation, hallucinations, nightmares, bad dreams.

Special senses
Eyes blurred, burning, light sensitive, swollen, aching, strained; ears–”clogged,” aching, tinnitus.

General
Increased appetite, weight loss, weight gain, yawning, somnolence, fever, dry mouth, head “pounding,” inguinal pain, swollen glands, “side” pains, cold feet, “hot spells.”

Post-marketing Experience

Data collected from post-marketing use of naltrexone hydrochloride show that most events usually occur early in the course of drug therapy and are transient. It is not always possible to distinguish these occurrences from those signs and symptoms that may result from a withdrawal syndrome.

Events that have been reported include anorexia, asthenia, chest pain, fatigue, headache, hot flushes, malaise, changes in blood pressure, agitation, dizziness, hyperkinesia, nausea, vomiting, tremor, abdominal pain, diarrhea, elevations in liver enzymes or bilirubin, hepatic function abnormalities or hepatitis, palpitations, myalgia, anxiety, confusion, euphoria, hallucinations, insomnia, nervousness, somnolence, abnormal thinking, dyspnea, rash, increased sweating, vision abnormalities and idiopathic thrombocytopenic purpura.

In some individuals the use of opioid antagonists has been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones. The clinical significance of such changes is not fully understood.

Adverse events, including withdrawal symptoms and death, have been reported with the use of naltrexone hydrochloride in ultra rapid opiate detoxification programs. The cause of death in these cases is not known (see WARNINGS).

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