MITOTANE, O, P' - DDD
Chemistry - Mitotane, also commonly known in veterinary medicine as o, p'-DDD, is structurallyrelated to the infamous insecticide, chlorophenothane (DDT). It occurs as a white, crystallinepowder with a slightly aromatic odor. It is practically insoluble in water and soluble in alcohol.
In dogs with pituitary-dependent hyperadrenocorticism (PDH), mitotane has been demonstrated tocause severe, progressive necrosis of the zona fasiculata and zona reticularis. These effects occurquite rapidly (within days of starting therapy). It has been stated that mitotane spares the zonaglomerulosa and therefore aldosterone synthesis is unaffected. This is only partially true, as thezona glomerulosa may also be affected by mitotane therapy, but it is uncommon for clinical ysignificant effects on aldosterone production to be noted with therapy.
Uses, Indications - In veterinary medicine, mitotane is used primarily for the medical treatment ofpituitary-dependent hyperadrenocorticism (PDH), principally in the dog. It has also been used forthe palliative treatment of adrenal carcinoma in humans and dogs.
Mitotane has a very long plasma half-life in humans, with values ranging from 18-159 days beingreported. Serum half-lives may increase in a given patient with continued dosing, perhaps due to adepot effect from adipose tissue releasing the drug. The drug is metabolized in the liver and isexcreted as metabolites in the urine and bile. Approximately 15% of an oral dose is excreted in thebile, and 10% in the urine within 24 hours of dosing.
Contraindications/Precautions - Mitotane is contraindicated in patients known to be hypersensitive to it. As it is unknown whether mitotane crosses the placenta, it should be used in pregnantbitches cautiously. As it is also unknown if the drug enters into milk, it's suggested that puppies begiven milk replacer after receiving colostrum if the mother is receiving mitotane.
Patients with concurrent diabetes mellitus may have rapidly changing insulin requirements duringthe initial treatment period. These animals should be closely monitored until they are clinical ystable.
Dogs with preexisting renal or hepatic disease should receive the drug with caution and with moreintense monitoring.
Some clinicians recommend giving prednisolone at 0.2 mg/kg/day during the initial treatmentperiod (0.4 mg/kg/day to diabetic dogs) to reduce the potential for side effects from acute endogenous steroid withdrawal. Other clinicians have argued that routinely administering steroidsmasks the clinical markers that signify when the endpoint of therapy has been reached and must bewithdrawn 2-3 days before ACTH stimulation tests can be done. Since in adequately observedpatients, adverse effects requiring glucocorticoid therapy may only be necessary in 5% of patients, the benefits of routine glucocorticoid administration may not be warranted.
Owners should be provided with a small supply of predniso(lo)ne tablets to initiate treatment.
Should the symptoms persist 3 hours after steroids are supplemented, consider other medicalproblems.
Liver changes (congestion, centrolobular atrophy, and moderate to severe fatty degeneration) havebeen noted in dogs given mitotane. Although not commonly associated with clinical symptomatology, these effects may be more pronounced with long-term therapy or in dogs with preexisting liver disease.
In perhaps 5% of dogs treated, long-term glucocorticoid and sometimes mineralocorticoid replacement therapy may be required. All dogs receiving mitotane therapy should receive additionalglucocorticoid supplementation if undergoing a stress (e.g., surgery, trauma, acute illness).
Overdosage - No specific recommendations were located regarding overdoses of this medication.
Because of the drug's toxicity and long half-life, emptying the stomach and administering charcoaland a cathartic should be considered after a recent ingestion. It is recommended that the patient beclosely monitored and given glucocorticoids if necessary.
If mitotane is used concomitantly with drugs that cause CNS depression, additive depressanteffects may be seen.
Diabetic dogs receiving insulin, may have their insulin requirements decreased when mitotanetherapy is instituted.
In dogs, spironolactone has been demonstrated to block the action of mitotane. It is recommended to use an alternate diuretic if possible.
Drug/Laboratory Interactions - Mitotane will bind competitively to thyroxine-binding globulinand decreases the amount of serum protein-bound iodine. Serum thyroxine concentrations may beunchanged or slightly decreased, but free thyroxine values remain in the normal range. Mitotanedoes not affect the results of the resin triiodothyronine uptake test.
Mitotane can reduce the amounts measurable 17-OHCS in the urine, which may or may not reflecta decrease in serum cortisol levels or adrenal secretion.
Storage, Stability, Compatibility
Mitotane tablets should be stored at room temperature (15-30°C), in tight, light resistant containers.Pharmacology - MITOTANE, O, P' - DDD
While mitotane is considered to be an adrenal cytotoxic agent, it apparently canalso inhibit adrenocortical function without causing cel destruction. The exact mechanisms ofaction for these effects are not clearly understood.In dogs with pituitary-dependent hyperadrenocorticism (PDH), mitotane has been demonstrated tocause severe, progressive necrosis of the zona fasiculata and zona reticularis. These effects occurquite rapidly (within days of starting therapy). It has been stated that mitotane spares the zonaglomerulosa and therefore aldosterone synthesis is unaffected. This is only partially true, as thezona glomerulosa may also be affected by mitotane therapy, but it is uncommon for clinical ysignificant effects on aldosterone production to be noted with therapy.
Uses, Indications - In veterinary medicine, mitotane is used primarily for the medical treatment ofpituitary-dependent hyperadrenocorticism (PDH), principally in the dog. It has also been used forthe palliative treatment of adrenal carcinoma in humans and dogs.
Pharmacokinetics - MITOTANE, O, P' - DDD
In dogs, the systemic bioavailability of mitonane is poor. Oral absorption canbe enhanced by giving the drug with food. In humans, approximately 40% of an oral dose ofmitotane is absorbed after dosing, with peak serum levels occuring about 3-5 hours after a singledose. Distribution of the drug occurs to virtually all tissues in the body. The drug is stored in the fatand does not accumulate in the adrenal glands. A small amount may enter the CSF. It is unknown ifthe drug crosses the placenta or is distributed into milk.Mitotane has a very long plasma half-life in humans, with values ranging from 18-159 days beingreported. Serum half-lives may increase in a given patient with continued dosing, perhaps due to adepot effect from adipose tissue releasing the drug. The drug is metabolized in the liver and isexcreted as metabolites in the urine and bile. Approximately 15% of an oral dose is excreted in thebile, and 10% in the urine within 24 hours of dosing.
Contraindications/Precautions - Mitotane is contraindicated in patients known to be hypersensitive to it. As it is unknown whether mitotane crosses the placenta, it should be used in pregnantbitches cautiously. As it is also unknown if the drug enters into milk, it's suggested that puppies begiven milk replacer after receiving colostrum if the mother is receiving mitotane.
Patients with concurrent diabetes mellitus may have rapidly changing insulin requirements duringthe initial treatment period. These animals should be closely monitored until they are clinical ystable.
Dogs with preexisting renal or hepatic disease should receive the drug with caution and with moreintense monitoring.
Some clinicians recommend giving prednisolone at 0.2 mg/kg/day during the initial treatmentperiod (0.4 mg/kg/day to diabetic dogs) to reduce the potential for side effects from acute endogenous steroid withdrawal. Other clinicians have argued that routinely administering steroidsmasks the clinical markers that signify when the endpoint of therapy has been reached and must bewithdrawn 2-3 days before ACTH stimulation tests can be done. Since in adequately observedpatients, adverse effects requiring glucocorticoid therapy may only be necessary in 5% of patients, the benefits of routine glucocorticoid administration may not be warranted.
Adverse Effects, Warnings
Most common adverse effects seen with initial therapy in dogs include lethargy, ataxia, weakness, anorexia, vomiting, and/or diarrhea. Adverse effects are commonlyassociated with plasma cortisol levels of less than 1 micrograms/dl or a too rapid decrease ofplasma cortisol levels into the normal range. Adverse effects may also be more commonly seen indogs weighing less than 5 kg, which may be due to the inability to accurately dose. The incidence ofone or more of these effects is approximately 25% and they are usually mild. If adverse effects arenoted, it is recommended to temporarily halt mitotane therapy and supplement with glucocorticoids.Owners should be provided with a small supply of predniso(lo)ne tablets to initiate treatment.
Should the symptoms persist 3 hours after steroids are supplemented, consider other medicalproblems.
Liver changes (congestion, centrolobular atrophy, and moderate to severe fatty degeneration) havebeen noted in dogs given mitotane. Although not commonly associated with clinical symptomatology, these effects may be more pronounced with long-term therapy or in dogs with preexisting liver disease.
In perhaps 5% of dogs treated, long-term glucocorticoid and sometimes mineralocorticoid replacement therapy may be required. All dogs receiving mitotane therapy should receive additionalglucocorticoid supplementation if undergoing a stress (e.g., surgery, trauma, acute illness).
Overdosage - No specific recommendations were located regarding overdoses of this medication.
Because of the drug's toxicity and long half-life, emptying the stomach and administering charcoaland a cathartic should be considered after a recent ingestion. It is recommended that the patient beclosely monitored and given glucocorticoids if necessary.
Drug Interactions
Mitotane may induce hepatic microsomal enzymes and, therefore, could increase the metabolism of certain drugs (e.g., barbiturates, warfarin).If mitotane is used concomitantly with drugs that cause CNS depression, additive depressanteffects may be seen.
Diabetic dogs receiving insulin, may have their insulin requirements decreased when mitotanetherapy is instituted.
In dogs, spironolactone has been demonstrated to block the action of mitotane. It is recommended to use an alternate diuretic if possible.
Drug/Laboratory Interactions - Mitotane will bind competitively to thyroxine-binding globulinand decreases the amount of serum protein-bound iodine. Serum thyroxine concentrations may beunchanged or slightly decreased, but free thyroxine values remain in the normal range. Mitotanedoes not affect the results of the resin triiodothyronine uptake test.
Mitotane can reduce the amounts measurable 17-OHCS in the urine, which may or may not reflecta decrease in serum cortisol levels or adrenal secretion.