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niLUTAmide
Nilutamide is a pure, specific nonsteroidal anti-androgen which blocks androgen binding to androgen receptors
Oral absorption: Yes, rapidly and completely
Pharmacokinetics are dose-related. Steady state achieved after two weeks.
| Cross blood brain barrier? | no information found |
| PPB | 84 % |
Liver, involves hepatic microsomal enzyme oxidation system.
| Active metabolites | hydroxymethylnitro derivative. |
| Inactive metabolites | yes |
Mainly in urine as metabolites; 1.4 - 7% in feces within 4-5 days.
| Urine | 62%, 3% unchanged |
| Half-life | 56 hours |
- Metastatic prostate cancer (stage D2, in conjunction with surgical castration)
Emetogenic Potential:
Extravasation Potential: Not applicable
The following adverse effects were reported in placebo-controlled clinical trials in conjunction with surgical/medical castration. Severe adverse effects from other studies or post-marketing may also be included.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Angina (2%) | E | |||
| Heart failure (1%) | E | ||||
| Hypertension (1%) | E | ||||
| Palpitations , tachycardia (rare) | E | ||||
| QT interval prolonged (with combined androgen blockade, rare) | E D | ||||
| Thromboembolism (1%) (stroke) | E | ||||
| Dermatological | Hirsutism (rare) | E | |||
| Pruritus (1%) | I E | ||||
| Rash (rare) | I E | ||||
| Gastrointestinal | Anorexia (1%) | E | |||
| Constipation (3%) | E | ||||
| Diarrhea (rare) | E | ||||
| Dry mouth (rare) | E | ||||
| Gastrointestinal pain (1%) | E | ||||
| Nausea, vomiting (4%) | I E | ||||
| General | Edema (2%) | E | |||
| Fatigue (1%) | E | ||||
| Other (4%) (alcohol intolerance) | I | ||||
| Hematological | Anemia (1%) | E D | |||
| Bone marrow hypocellular (aplastic anemia - very rare) | E D | ||||
| Hepatobiliary | Hepatic failure (<1%) | D | |||
| ↑ LFTs (2%) | E | ||||
| Metabolic / Endocrine | Hyperglycemia (1%) | E | |||
| Musculoskeletal | Other - Bone loss (rare, after long-term use) | L | |||
| Nervous System | Anxiety (rare) | E | |||
| Depression (1%) | E | ||||
| Dizziness (3%) | E | ||||
| Headache (3%) | E | ||||
| Sleep disorder (1%) | E | ||||
| Ophthalmic | Eye disorders (11%) (retarded light-to-dark adaptation) | E | |||
| Other (3%) (visual disturbances) | E | ||||
| Photophobia (1%) | E | ||||
| Reproductive and breast disorders | Erectile dysfunction (1%) | E | |||
| Gynecomastia (1%) | E | ||||
| Respiratory | Dyspnea (1%) | E | |||
| Pneumonitis / Interstitial Lung Disease (1%) | D | ||||
| Vascular | Hot flashes (14%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for niLUTAmide include hot flashes, eye disorders, nausea, vomiting, constipation, dizziness, headache, other, ↑ lfts and edema.
Retarded light-to-dark adaptation usually improves on treatment, and usually resolves when treatment is discontinued. Patients should be cautioned about driving at night or through tunnels. This effect can be alleviated by wearing tinted glasses.
Bone loss may occur during the hypoandrogenic state caused by long-term use of nilutamide. Risk factors such as older age, pre-existing osteopenia, family history of osteoporosis, chronic use of corticosteroids, anticonvulsants, or other drugs that may lead to osteoporosis or chronic alcohol/tobacco abuse should be carefully considered before starting treatment.
Androgen deprivation may increase cardiovascular risk (MI, sudden death, stroke) in men with prostate cancer since it can adversely affect cardiovascular risk factors, such as increased body weight, reduced insulin sensitivity and/or dyslipidemia.
QTc prolongation has been described with combined androgen blockade and nilutamide should be used with caution in patients with other risk factors such as congenital long QT syndrome, abnormal electrolytes and concomitant medications which prolong QTc.
Reduction in glucose tolerance and increased risk of developing diabetes have been reported in men treated with androgen deprivation therapy. Anemia is also a known physiologic effect of testosterone suppression.
Interstitial pneumonitis has been described, with an apparently higher incidence in patients of Japanese origin (13%). It generally occurs within the first 3 months of therapy, and may resolve after treatment discontinuation or lead to death in some cases. Interrupt nilutamide treatment if new or worsening dyspnea or other signs of pneumonitis occur. Treatment should be discontinued if pneumonitis is diagnosed, and the use of steroids should be considered. Patients of Japanese origin may also be at a high risk of liver function test abnormalities (19%). Hepatotoxicity generally occurs 3-4 months after starting nilutamide, and results in drug discontinuation in 1% of patients.
Antiandrogen withdrawal syndrome has been described; after discontinuation for disease progression, 6-8 weeks should elapse before making further treatment decisions.
Refer to protocol by which patient is being treated.
Oral:
- Initial: 300mg daily for 30 days*, then
- Maintenance: 150mg once daily
(* may start maintenance earlier should intolerance occur)
| Toxicity | Dose Adjustment |
| Myelosuppression | No adjustment required |
| Suspected pneumonitis | Hold, investigate and treat appropriately; discontinue if confirmed |
| QT prolongation | Discontinue |
If transaminases >2-3x upper limit of normal, interrupt treatment and monitor liver function closely. Discontinue if severe hepatic impairment.
No adjustment required.
No adjustment required.
A higher rate of interstitial pneumonitis and elevated transaminases were reported in Japanese patients. Use with caution when treating Asian patients.
Contraindicated
- Take tablet(s) by mouth, before breakfast.
- Avoid alcoholic beverages during treatment.
- If a dose is missed, the next dose should be taken at the usual time. A double dose should not be taken to make up for missed doses.
- Store between 15 to 30°C.
- Patients with known hypersensitivity to the drug or to any constituents of the drug product.
- Patients with severe hepatic dysfunction or with severe respiratory insufficiency.
- Nilutamide is contraindicated in women and children.
- Contains lactose; should not be used in patients with hereditary galactose/glucose/lactase disorders.
- Patients taking nilutamide should be warned against consuming alcohol because of a possible disulfiram-like reaction.
- Patients should be advised regarding impairment of light adaptation if they plan to operate a vehicle or machinery.
- Nilutamide should not be administered to patients with congenital long QT syndrome, and should be discontinued in patients who develop QT prolongation.
-
Fertility effects:
Probable
- Nilutamide should not be used by women. In the laboratory, this drug may harm or affect the embryos or offspring of animals exposed to it.
- If there is a chance of pregnancy in a female partner, adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose (general recommendation)
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Alcohol | Possible disulfiram-like reaction (4%) | Unknown | Avoid |
| Drugs metabolized by hepatic microsomal enzymes (e.g., warfarin, phenytoin, propranolol, chlordiazepoxide, lidocaine, diazepam, theophylline) | Possible ↑ in serum levels of these drugs if given with nilutamide | Inhibition of CYP2C19 by nilutamide | Monitor for increased pharmacological effect/toxicity with drugs that have a narrow therapeutic index; adjust doses as required |
| Drugs that increase QT interval | ↑ risk of QT prolongation or Torsades de pointes | Additive | Caution; monitor closely |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests |
Baseline and as clinically indicated |
Blood glucose levels/HbA1c |
Baseline and at each visit, especially in diabetic patients |
EKG, Electrolytes (including K, Ca, Mg) |
Baseline, and regularly for at risk patients |
Chest X-ray +/- pulmonary function tests |
Baseline and as clinically indicated |
Clinical toxicity assessment for androgen deprivation symptoms, ocular and respiratory effects, and cardiovascular effects. |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
INR for patients on warfarin |
Baseline and as clinically indicated |
Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA).
Nilutamide: e-Drugdex, Micromedex Healthcare Series.
McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1188-9.
Product Monograph: Anandron® (nilutamide). Sanofi-aventis Canada Inc., June 13, 2016.
Nilutamide. Lexi-Drugs Online. Lexicomp Inc. Updated July 13, 2018.
September 2018 Updated adverse effects, monitoring and administration
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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