INFORMATION FOR HEALTH PROFESSIONALS
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The sponsor (pharmaceutical company) of this product has advised Medsafe that this product has
either been discontinued or is no longer marketed in New Zealand.
Therefore this Data Sheet may not be up to date.
Medsafe has elected to leave it on this web site because supplies of this product may still be available, and health
professionals should continue to have access to this product information in the interim.
You may be able to find a more current Data Sheet containing the same medicine by returning to the main Data Sheet
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Hexalen® 50 mg capsules are available in 50 mg strength capsules of altretamine for oral administration.
The precise mechanism by which Hexalen® exerts its cytotoxic effect is unknown, although a number of theoretical possibilities have been studied. Structurally, Hexalen® resembles the alkylating agent triethylenemelamine, yet in vitro tests for alkylating activity of Hexalen® and its metabolites have been negative. Hexalen® has been demonstrated to be efficacious for certain ovarian tumours resistant to classical alkylating agents. Metabolism of altretamine is a requirement for cytotoxicity. Synthetic monohydroxymethylmelamines, and products of altretamine metabolism, in vitro and in vivo, can form covalent adducts with tissue macromolecules including DNA, but the relevance of these reactions to antitumor activity is unknown.
Hexalen® is well-absorbed following oral administration in humans, but undergoes rapid and extensive demethylation in the liver, producing variation in altretamine plasma levels. The principal metabolites are pentamethylmelamine and tetramethylmelamine.
Pharmacokinetic studies were performed in a limited number of patients and should be considered preliminary. After oral administration of Hexalen® to 11 patients with advanced ovarian cancer in doses of 120-300mg/m², peak plasma levels (as measured by gas-chromatographic assay) were reached between 0.5 and 3hours, varying from 0.2 to 20.8mg/l. The half-life ranged from 4.7 to 10.2 hours. Altretamine and metabolites show binding to plasma proteins. The free fractions of altretamine, pentamethylmelamine and tetramethylmelamine are 6%, 25% and 50%, respectively.
Following oral administration of 14C-ring-labelled altretamine (4 mg/kg), urinary recovery of radioactivity was 61% at 24 hours and 90% at 72 hours. Human urinary metabolites were N-demethylated homologues of altretamine with <1% unmetabolized altretamine excreted at 24 hours.
After intraperitoneal administration of 14C-ring-labelled altretamine to mice, tissue distribution was rapid in all organs, reaching a maximum at 30 minutes. The excretory organs (liver and kidney) and the small intestine showed high concentrations of radioactivity, whereas relatively low concentrations were found in other organs, including the brain.
There have been no formal pharmacokinetic studies in patients with compromised hepatic and/or renal function, though Hexalen® has been administered both concurrently and following nephrotoxic drugs such as cisplatin.
Hexalen® has been administered in 4 divided doses, with meals and at bedtime, though there is no pharmacokinetic data on this schedule nor information from formal interaction studies about the effect of food on its bioavailability or pharmacokinetics.
In two studies in patients with persistent or recurrent ovarian cancer following first-line treatment with cisplatin and/or alkylating agent-based combination, Hexalen® was administered as a single agent for 14 or 21 days of a 28 day cycle. In the 51 patients with measurable or evaluable disease, there were 6 clinical complete responses, 1 pathologic completed response, and 2 partial responses for an overall response rate of 18%. The duration of these responses ranged from 2 months in a patient with a palpable pelvic mass to 36 months in a patient who achieved a pathologic complete response. In some patients, tumour regression was associated with improvement in symptoms and performance status.
Hexalen® is indicated for the treatment of Advanced Stage (Stage III and IV) ovarian tumours, to be employed as follows:
Hexalen® is administered orally. Doses are calculated on the basis of body surface area or weight.
REPRESENTATIVE DOSE SCHEDULES FOR METASTATIC OVARIAN CARCINOMA:
In combination:
For patients who cannot tolerate a platinum-based regimen, effective therapy can be achieved with the HAC regimen.
| Hexalen® | 150 mg/m² po on days 1 to 14 |
| Doxorubicin hydrochloride | 50 mg/m² IV on day 1 |
| Cyclophosphamide | 70 mg/m² po on days 1 to 14. |
Therapy is repeated every 28 days, assuming return of blood counts.
As a single agent:
As a single agent, Hexalen® may be administered either for 14 or 21 consecutive days in a 28 day cycle at a dose of 260mg/m². The total daily dose may be given as 4 divided oral doses after meals and at bedtime. There is no pharmacokinetic information supporting this dosing regime and the effect of food on Hexalen® bioavailability or pharmacokinetics has not been evaluated.
Hexalen® should be temporarily discontinued (for 14 days or longer) and subsequently restarted at 200mg/m²/day if any of the following situations occur:
If neurologic symptoms fail to stabilize on the reduced dose schedule, Hexalen® should be discontinued indefinitely.
Procedures for proper handling and disposal of anticancer drugs should be considered.
Hexalen® is contraindicated in patients who have shown hypersensitivity to altretamine or to any of the other ingredients in the capsules (see DESCRIPTION ).
Hexalen® should not be employed in patients with preexisting severe bone marrow depression or severe neurologic toxicity. Hexalen® has been administered safely, however, to patients heavily pretreated with cisplatin and/or alkylating agents, including patients with preexisting cisplatin neuropathies. Careful monitoring of neurologic function in these patients is essential.
Hexalen should not be administered to patients who are pregnant or breast-feeding (see PRECAUTIONS - Use in pregnancy and Use in lactation ).
Hexalen® should only be given under the supervision of a physician experienced in the use of antineoplastic agents.
Peripheral blood counts should be monitored at least monthly, prior to the initiation of each course of Hexalen®, and as clinically indicated (see ADVERSE REACTIONS ).
Because of the possibility of Hexalen®-related neurotoxicity, neurologic examination should be performed regularly during Hexalen® administration (see ADVERSE REACTIONS ). Administration of Hexalen should only be considered in patients with pre-existing severe neurological toxicity after the risks and benefits have been considered.
Concurrent administration of Hexalen® and antidepressants of the monoamine oxidase (MAO) inhibitor class may cause severe orthostatic hypotension. Four patients, all over 60 years of age, were reported to have experienced symptomatic hypotension after 4 to 7 days of concomitant therapy with Hexalen® and MAO inhibitors.
Oral administration of Hexalen® to rats at doses of 60-240 mg/m²/day for 4 weeks or longer resulted in a diabetic syndrome characterised by vacuolization and disappearance of insulin granules in the β-cells of pancreatic islets resulting in severe hyperglycaemia. Ultrastructural changes in the β-cells were observed following treatment at 480 mg/m²/day for 7 days.
Hexalen therapy may cause bone marrow suppression; lower doses may be necessary if bone marrow suppression occurs. The bone marrow depressant effects of Hexalen may increase the incidence of microbial infection, delayed healing and gingival bleeding.
Wherever possible, dental work should be completed before Hexalen therapy is initiated, or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during Hexalen treatment, including caution in teeth brushing, and use of dental floss or toothpicks.
The risks and benefits should be considered before patients with an infection are treated with Hexalen, due to its immunosuppressive effects. Hexalen should be administered with caution to patients with herpes zoster or with existing or recent chicken pox (including recent exposure), as there is a risk that severe generalised disease will develop.
Immunisation of patients being treated with Hexalen should only be undertaken with extreme caution, after a careful review of the patient's haematologic status, as Hexalen may suppress normal defence mechanisms. Concurrent use of Hexalen with live virus vaccines may potentate the replication of the vaccine virus, increase adverse effects of the vaccine virus, and /or may decrease the patient's antibody response to the vaccine. Hexalen may also decrease the patient's antibody response to killed virus vaccines. The interval between discontinuation of medications that cause immune suppression and restoration of the patient's ability to respond to the vaccine depends on many factors; estimates vary from three months to one year. Patients with leukemia which is in remission should not receive live virus vaccines until at least three months after their last chemotherapy treatment.
People in close contact with a patient who is being treated with Hexalen, especially family members, should postpone immunisation with oral polio vaccines.
Caution should also be used in patients who have had previous cytotoxic drug therapy or radiation therapy.
Pregnancy Category D. Hexalen should not be administered to patients who are pregnant. Hexalen® has been shown to be embryotoxic in rats (at about 142-570mg/m²/day) and rabbits (at about 1040mg/m²/day) and teratogenic in rats (at about 570mg/m²/day). Hexalen® may cause foetal damage when administered to a pregnant woman. If Hexalen® is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be appraised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant.
It is not known whether altretamine is excreted in human or animal milk. In a rat study, pup weight gains during lactation were reduced when dams were treated with 62 and 124 mg/m²/day of Hexalen® from prior to mating to the end of gestation. Because there is a possibility of toxicity in nursing infants secondary to Hexalen® treatment of the mother, it is recommended that breast feeding be discontinued if the mother is treated with Hexalen®.
The safety and effectiveness of Hexalen® in children has not been established.
Hexalen should be used with caution in patients with hepatic or renal impairment. Severe hepatic function impairment will reduce activation and/or metabolism of Hexalen. Elimination may be reduced as a result of renal function impairment.
Since Hexalen® treatment may cause fatigue it may impair the patients ability to drive and use machinery under certain circumstances.
The carcinogenic potential of Hexalen® has not been studied in animals, but many alkylating agents, including the structurally-related agent triethylenemalamine, have been shown to be carcinogenic. Hexalen® was weakly mutagenic when tested in strain TA100 of Salmonella typhimurium. At a dose of 120mg/m²/day, Hexalen® administered to female rats 14 days prior to breeding through the gestation period had no adverse effect on fertility but decreased post-natal survival. Hexalen® was embryocidal at a dose of 240mg/m²/day. Administration of 120mg/m²/day Hexalen® to male rats for 60 days prior to mating resulted in testicular atrophy, reduced fertility and a possible dominant lethal mutagenic effect. Furthermore in another study, oral treatment of male rats with 120mg/m²/day of Hexalen® for 62 days prior to mating was associated with reduced fertility, testicular atrophy and focal or diffuse aspermatogenesis. Administration of 460-1800 mg/m²/day to male rats for 10 days had decreased spermatogenesis, atrophy of testes, seminal vesicles and ventral prostate.
With continuous high-dose daily Hexalen®, nausea and vomiting of gradual onset occurs frequently. Although in most instances these symptoms are controllable with anti-emetics, at times the severity requires Hexalen® dose reduction or, rarely, discontinuation of Hexalen® therapy. In some instances, a tolerance of these symptoms develops after several weeks of therapy. The incidence and severity of nausea and vomiting are reduced with moderate dose administration of Hexalen®. In 2 clinical studies of single-agent Hexalen® utilising a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued Hexalen® due to severe nausea and vomiting.
Diarrhoea, loss of appetite, stomach cramps and renal toxicity have also been reported.
Asymptomatic hepatotoxicity is rare, but has been reported.
Peripheral neuropathy and central nervous system symptoms (depression, confusion, disorders of consciousness, ataxia, dizziness, vertigo, hallucinations, anxiety, clumsiness, weakness, numbness in arms and legs and, rarely, seizures) have been reported. They are more likely to occur in patients receiving continuous high-dose daily Hexalen® than moderate dose Hexalen® administered on an intermittent schedule. Neurologic toxicity has been reported to be reversible when therapy is discontinued. Data from a randomised trial of Hexalen® and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response furcation suggesting that pyridoxine should not be administered with Hexalen® and/or cisplatin.
Hexalen® causes mild to moderate dose-related myelosuppression. Bone marrow depression manifests as leucopenia, thrombocytopenia and anaemia, which are often asymptomatic. Leucopenia may appear, less commonly or rarely, as fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination. Thrombocytopenic symptoms include unusual bleeding or bruising, black tarry stools, blood in the urine or faeces, or pinpoint red spots on the skin. Anaemia may manifest as unusual tiredness.
Leukopenia below 3,000 WBC/mm³ occurred in less than 15% of patients on a variety of intermittent or continuous dose regimens. Less than 1% had leukopenia below 1,000 WBC/mm³. Thrombocytopenia below 50,000 platelets/mm³ was seen in less than 10% of patients. When given in doses of 8-12mg/kg/day over a 21 day course, nadirs of leukocyte and platelet counts were reached by 3 to 4 weeks, and normal counts were regained by 6 weeks. With continuous administration, nadirs are reached in 6 to 8 weeks (median).
Skin rash and itching are rare, but have been reported.
Data in the following table are based on the experience of 76 patients with ovarian cancer previously treated with a cisplatin-based combination regimen who received single-agent HEXALEN. In one study, HEXALEN, 260mg/m²/day, was administered for 14 days of a 28 day cycle. In another study, HEXALEN, 6-8mg/kg/day, was administered for 21 days of a 28 day cycle.
ADVERSE EXPERIENCES IN 76 PREVIOUSLY TREATED
OVARIAN CANCER PATIENTS RECEIVING SINGLE-AGENT HEXALEN
| Gastrointestinal | % |
|---|---|
| Nausea and Vomiting | 33 |
| Mild to Moderate | 32 |
| Severe | 1 |
| Increased Alkaline Phosphatase | 9 |
| Neurologic | |
| Peripheral Sensory Neuropathy | 31 |
| Mild | 22 |
| Moderate to Severe | 9 |
| Anorexia and Fatigue | 1 |
| Seizures | 1 |
| Haematologic | |
| Leukopenia | 5 |
| WBC 2000-2999/mm³ | 4 |
| WBC <2000/mm³ | 1 |
| Thrombocytopenia | 9 |
| Platelets 75,000-99,000/mm³ | 6 |
| Platelets <75,000/mm³ | 3 |
| Anaemia | 33 |
| Mild | 20 |
| Moderate to Severe | 13 |
| Renal | |
| Serum creatinine 1.6-3.75 mg/dl | 7 |
| BUN | 9 |
| 25-40 mg% | 5 |
| 41-60mg% | 3 |
| >60mg% | 1 |
Additional adverse reaction information is available from 13 single-agent altretamine studies (total of 1014 patients)
conducted under the auspices of the National Cancer Institute. The treated patients had a variety of tumours and many
were heavily pretreated with other chemotherapies; most of these trials utilized high, continuous daily doses of
altretamine (6-12mg/kg/day). In general, adverse reaction experiences were similar in the two trails described above.
Additional toxicities, not reported in the above table, included hepatic toxicity, skin rash, pruritus and alopecia,
each occurring in <1% of patients.
Concurrent administration of Hexalen® and antidepressants of the MAO inhibitor class may cause severe orthostatic hypotension (see PRECAUTIONS ).
Cimetidine, an inhibitor of microsomal drug metabolism, increased altretamine's half-life and toxicity in a rat model.
Pyridoxine reduces the cytotoxic activity of Hexalen. Data from a randomised trial of Hexalen® and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pyridoxine should not be administered with Hexalen® and/or cisplatin.
The leucopenic and/or thrombocytopenic effects of Hexalen may be increased as a result of concurrent therapy with other medications which cause blood dyscrasias; dosage adjustments of Hexalen, if necessary, should be based on blood counts.
Concurrent administration of Hexalen and other bone marrow depressants, including radiation therapy, may lead to additive bone marrow depression. Dosage adjustment may be necessary when two or more bone marrow depressants are used concurrently or consecutively.
The patient's antibody response to killed virus vaccines may be decreased if these vaccines are administered concurrently with Hexalen (see PRECAUTIONS ).
As a result of its effects on the gastrointestinal mucosa, Hexalen may interfere with the absorption of drugs which are given orally.
Peripheral blood counts should be monitored at least monthly, prior to the initiation of each course of Hexalen®, and as clinically indicated (see ADVERSE REACTIONS ).
No case of acute overdosage in humans has been described. The oral LD50 dose for the micronized form of altretamine was 6300mg/m² (1050mg/kg) in rats and 1311mg/m² (437mg/kg) in mice.
Overdosage with Hexalen® would be expected to produce effects, which are an extension of the pharmacological effects. The toxic reactions expected would include those listed under ADVERSE EFFECTS.
Store below 30°C. Keep bottle tightly closed.
Prescription Medicine
50 mg strength capsules of altretamine for oral administration.
Hexalen capsules contain lactose, calcium stearate, gelatin, silicon dioxide, sodium lauryl sulfate and Opacode 5-1-4116 (blue marking ink).
The chemical structure of altretamine is shown below:
Mayne Pharma (NZ) Limited
23 Haining Street
Te Aro
Wellington
New Zealand
1 October 2006