Hivid (Zalcitabine)

HIVID®

Roche

Zalcitabine

Antiretroviral Agent

Action And Clinical Pharmacology: Zalcitabine is a synthetic nucleoside analogue of the naturally occurring nucleoside 2-deoxycytidine in which the 3-hydroxyl group is replaced by hydrogen. Within cells, zalcitabine is converted to the active metabolite, dideoxycytidine 5-triphosphate (ddCTP), by cellular enzymes. ddCTP serves as an alternative substrate to deoxycytidine triphosphate (dCTP) for HIV-reverse transcriptase and inhibits the in vitro replication of HIV-1 by inhibition of viral DNA synthesis. This inhibition has been demonstrated in vitro in human primary cell cultures and in established cell lines. In DNA biosynthesis, DNA chain extension occurs through the formation of a phosphodiester bridge between the 3-hydroxyl group of the growing end of a DNA chain and the 5-phosphate group of the incoming deoxynucleotide. Because ddCTP lacks the 3-hydroxyl group required for chain elongation, its incorporation into a growing DNA chain leads to premature chain termination. ddCTP serves as a competitive inhibitor of the natural substrate, dCTP, for the active site of the viral reverse transcriptase and thus further inhibits viral as well as cellular DNA synthesis.

Cellular mitochondrial DNA polymerase gamma has a high affinity for the active metabolite, ddCTP, which has been reported to be incorporated into the DNA of cells in culture. However, DNA chain termination with cellular DNA polymerases has not been demonstrated. The half-life of ddCTP in established cell lines and in human peripheral blood mononuclear cells in culture has been determined to be in the range of 2.6 to 10 hours.

Indications And Clinical Uses: Monotherapy for Zidovudine Intolerant or Zidovudine Failures in Advanced HIV Infection: Zalcitabine is indicated for the treatment of adult patients with advanced HIV infection who have demonstrated intolerance or significant clinical or immunologic deterioration during zidovudine therapy.

Combination Therapy with Zidovudine in Advanced HIV Infection: Zalcitabine in combination with zidovudine is indicated for the treatment of selected patients with advanced HIV disease (CD4 cell counts 300 cells/mm.

In zidovudine-naive patients this indication is based on greater increases in CD4 cell counts that were maintained longer for patients treated with combination therapy as compared to zidovudine monotherapy. There have been no studies showing clinical benefit from combination therapy in zidovudine-naive patients. For patients with prior zidovudine exposure, this indication is based on a subgroup analysis of clinical data that showed a clinical benefit only for those patients with a CD4 count ³150 cells/mmat the time of the initiation of therapy.

Contra-Indications: In patients with clinically significant hypersensitivity to zalcitabine or to any of the components of the formulation.

Manufacturers’ Warnings In Clinical States: In patients who have shown clinical or immunologic deterioration while receiving zalcitabine as monotherapy or in combination with zidovudine, consideration should be given to the use of alternative antiretroviral therapy.

The major clinical toxicities of zalcitabine are peripheral neuropathy and much less frequently, pancreatitis. Rare occurrences of hepatic toxicity have also been reported with the use of nucleoside analogues, including zidovudine and zalcitabine. Toxicities previously associated with zidovudine monotherapy are likely to occur in patients treated with combined zalcitabine and zidovudine therapy. It is recommended that physicians refer to the product monograph for zidovudine before prescribing combination therapy with zalcitabine and zidovudine.

The decision to use zalcitabine should be made in consultation with a physician experienced in the care of patients with HIV infection.

Peripheral Neuropathy: The major clinical toxicity of zalcitabine, possibly or probably related to drug treatment, is peripheral neuropathy which occurred in 21 to 36% of subjects who received monotherapy zalcitabine in Phase 2 and 3 clinical studies. Moderate to severe peripheral neuropathy was noted in 20 to 23% of these subjects. By comparison, neuropathy occurred in as many as 19% of patients treated with monotherapy zidovudine, and in up to 10% of these patients, the neuropathy was moderate to severe. When combined zalcitabine and zidovudine were used, the occurrence of peripheral neuropathy was similar to that which was seen with monotherapy zalcitabine (i.e., 21 to 28%, with 4 to 19% classified as moderate to severe).

Zalcitabine-related peripheral neuropathy is a sensorimotor neuropathy characterized initially by numbness and burning dysesthesia involving the distal extremities. These symptoms may be followed by sharp shooting pains or severe continuous burning pain if the drug is not withdrawn. The neuropathy may progress to severe pain requiring narcotic analgesics and is potentially irreversible, especially if zalcitabine is not stopped promptly. In some patients, symptoms of neuropathy may initially progress despite discontinuation of zalcitabine. With prompt discontinuation of zalcitabine the neuropathy is usually slowly reversible.

There are no data regarding the use of zalcitabine in patients with pre-existing peripheral neuropathy since these patients were excluded from clinical trials; therefore, zalcitabine should be used with extreme caution in these patients.

Zalcitabine should be stopped promptly when moderate discomfort from numbness, tingling, burning or pain of the extremities progresses, or any related symptoms occur that are accompanied by an objective finding. Peripheral neuropathy requiring zalcitabine interruption is defined as moderate discomfort of the lower extremities (requiring non-narcotic analgesics) that is bilateral and persists for ³3 days, or mild symptoms accompanied by the loss of a previously present Achilles reflex. If symptoms resolve to mild intensity, rechallenge with half-dosage is permitted. Peripheral neuropathy requiring permanent discontinuation of zalcitabine is defined as any severe discomfort of the extremities requiring narcotic analgesics, or moderate discomfort progressing for 1 week.

Pancreatitis: Documented fatal pancreatitis has been observed with the administration of zalcitabine alone or the combination of zalcitabine with zidovudine. Pancreatitis is an uncommon complication of zalcitabine monotherapy, occurring in 1.1% of patients. The occurrence of asymptomatic elevated serum amylase of any etiology while on zalcitabine monotherapy was 1.6%. Among patients treated with zalcitabine in the expanded access safety study who had a history of prior pancreatitis or increased amylase, 5.3% developed pancreatitis and an additional 4.4% developed asymptomatic elevated serum amylase. There was no apparent difference in the occurrence of pancreatitis between the 2 doses of zalcitabine (2.25 mg or 1.125 mg daily) used in the Expanded Access trial.

Caution should be exercised when administering zalcitabine to any patient with a history of pancreatitis or a known risk factor for the development of pancreatitis. There have been isolated cases of death from fulminant pancreatitis. In one case, the patient was treated with combination zalcitabine and zidovudine; in a second case, the patient was treated concomitantly with i.v. pentamidine and zalcitabine.

All patients receiving i.v. pentamidine for the treatment of P. carinii pneumonia (PCP) should have zalcitabine treatment interrupted for the period of pentamidine administration.Treatment with zalcitabine should also be interrupted if therapy with another drug known to cause pancreatitis is required (see Precautions, Drug Interactions).

Patients with a history of pancreatitis or a history of elevated serum amylase should be followed more closely while on zalcitabine therapy. The significance of an asymptomatic increase in serum amylase levels in HIV-infected patients prior to starting zalcitabine or while on zalcitabine is unclear. Treatment with zalcitabine should be interrupted in the setting of a rising serum amylase level associated with dysglycemia, rising triglycerides level, decreasing serum calcium or other parameters or symptoms suggestive of impending pancreatitis, until a clinical diagnosis is reached.

Treatment with zalcitabine should be stopped immediately if nausea, vomiting, abdominal pain or other symptoms suggestive of pancreatitis develop, until a definitive diagnosis can be established. Zalcitabine should be restarted only after pancreatitis has been ruled out. If clinical pancreatitis develops during zalcitabine administration, it is recommended that zalcitabine be permanently discontinued.

Hepatic Toxicity: Rare occurrences of lactic acidosis in the absence of hypoxemia and severe hepatomegaly with steatosis have been reported with the use of nucleoside analogues, including zidovudine and zalcitabine, and are potentially fatal. In addition, rare cases of hepatic failure (1 which coincided with renal failure) and death considered possibly related to underlying hepatitis B and zalcitabine monotherapy have been reported.

Treatment with zalcitabine in patients with pre-existing liver disease, liver enzyme abnormalities, a history of ethanol abuse or hepatitis should be interrupted or discontinued in the setting of deterioration of liver function tests, hepatic steatosis, progressive hepatomegaly or unexplained lactic acidosis. In clinical trials, drug interruption was recommended if liver function tests exceeded 5 times the upper limit of normal.

Other Serious Toxicities: Oral Ulcers: Severe oral ulcers occurred in approximately 3% of patients receiving zalcitabine in 2 clinical studies; less severe oral ulcerations have occurred at higher frequencies in other clinical trials.

Esophageal Ulcers: Infrequent cases of esophageal ulcers have been attributed to zalcitabine therapy. Interruption of zalcitabine should be considered in patients who develop esophageal ulcers that do not respond to specific treatment for opportunistic pathogens in order to assess a possible relationship to zalcitabine.

Cardiomyopathy/Congestive Heart Failure: Cardiomyopathy and congestive heart failure in patients with AIDS have been associated with the use of nucleoside antiretroviral agents. Infrequent cases have been reported in patients receiving zalcitabine. In one case, the investigator considered that the exacerbation of preexisting cardiomyopathy was possibly related to zalcitabine. Treatment with zalcitabine in patients with baseline cardiomyopathy or a history of congestive heart failure should be approached with caution.

Anaphylactoid Reaction: There has been one report of an anaphylactoid reaction occurring in a patient receiving both zalcitabine and zidovudine in an alternating regimen. In addition, there have been several reports of urticaria without other signs of anaphylaxis.

Because severe adverse effects may be attributable to either zalcitabine or zidovudine singly or to their combination, the complete prescribing information for zidovudine should be consulted before initiation of combination therapy or reinstitution of monotherapy with zidovudine following an adverse reaction.

Precautions: General: Patients receiving zalcitabine or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV disease.

Lymphoma: High doses of zalcitabine, administered for 3 months to B6C3F1 mice (resulting in plasma concentrations over 1 000 times those seen in patients taking the recommended doses of zalcitabine) induced an increased incidence of thymic lymphoma. Although the pathogenesis of the effect is uncertain, a predisposition to chemically induced thymic lymphoma and high rates of spontaneous lymphoreticular neoplasms have previously been noted in this strain of mice.

The incidence of lymphomas was reviewed in 13 comparative and 7 expanded-access studies using zalcitabine. In one study a statistically significant increase in the rate of lymphomas was seen in patients receiving zalcitabine or combination zalcitabine and zidovudine compared to zidovudine alone (rates of 0, 1.3 and 2.3 per 100 person years were recorded for zidovudine, zalcitabine, and combination zalcitabine/zidovudine, respectively. Based on a review of the literature, the expected incidence of lymphomas in HIV infected patients with advanced disease on zidovudine monotherapy would be approximately 1 to 2 per 100 person years of follow-up.

Children: The safety and effectiveness of zalcitabine in combination with zidovudine or as monotherapy in HIV-infected children younger than 13 years of age has not been established.

Pregnancy: There are no adequate and well-controlled studies of zalcitabine use in pregnant women. Zalcitabine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Fertile women should not receive zalcitabine unless they are using effective contraception during therapy.

Zalcitabine has been shown to be teratogenic in mice at calculated exposure levels of 1 365 and 2 730 times of those achieved with the maximum recommended human dose (MRHD) based on AUC measurements. In rats, zalcitabine was teratogenic at a calculated exposure level of 2 142 times the MRHD but not at an exposure level of 485 times the MRHD.

In a perinatal and postnatal study in the rat, a high incidence of hydrocephalus was observed in the F1 offspring derived from the litters of dams treated with 1 071 times the MRHD (based on AUC measurements) but not at an exposure level of 485 times the MRHD.

Increased embryolethality was observed in pregnant mice at doses 2 730 times the MRHD and in rats above 485 times the MRHD (based on AUC measurements). Average fetal body weight was significantly decreased in mice at doses of 1 365 times the MRHD and in rats at 2 142 times the MRHD.

Lactation: It is not known whether zalcitabine is excreted in human milk. Because of uncertainties related to transmission of virus and to excretion of zalcitabine in breast milk, it is advisable to caution mothers against breast-feeding.

Patients with Special Diseases and Conditions:

Hepatic Impairment: The use of zalcitabine may be associated with exacerbation of hepatic dysfunction especially in individuals with pre-existing liver disease, liver enzyme abnormalities, a history of ethanol abuse, or hepatitis. In such patients, zalcitabine should be interrupted or discontinued in the setting of deteriorating liver function tests (LFTs), hepatic steatosis, progressive hepatomegaly or unexplained lactic acidosis. Of 85 patients in the expanded access safety study with a prior history of LFT elevation before starting zalcitabine, 10 (12%) developed increases in LFTs greater than 5 times the upper limit of normal while on zalcitabine. In clinical trials, drug interruption was recommended if LFTs exceeded 5 times the upper limit of normal (see Warnings, Hepatic Toxicity).

Drug Interactions: The concomitant use of zalcitabine with drugs that have the potential to cause peripheral neuropathy should be avoided where possible. Drugs which have been associated with peripheral neuropathy include chloramphenicol, cisplatin, dapsone, disulfiram, ethionamide, glutethimide, gold, hydralazine, iodoquinol, isoniazid, metronidazole, nitrofurantoin, phenytoin, ribavirin, and vincristine. Concomitant use of zalcitabine with didanosine is not recommended.

Drugs such as amphotericin, foscarnet, and aminoglycosides may increase the risk of developing peripheral neuropathy or other zalcitabine-associated toxicities by interfering with the renal clearance of zalcitabine (and thereby raising systemic exposure). Patients who require the use of one of these drugs with zalcitabine should have frequent clinical and laboratory monitoring with dosage adjustment for any significant change in renal function.

Treatment with zalcitabine should be interrupted when the use of a drug that has the potential to cause pancreatitis is required. Death due to fulminant pancreatitis possibly related to zalcitabine and i.v. pentamidine was reported. If i.v. pentamidine is required to treat P. carinii pneumonia, treatment with zalcitabine should be interrupted for the period of pentamidine administration (see Warnings).

Concomitant administration of probenecid or cimetidine decreases the elimination of zalcitabine, most likely by inhibition of renal tubular secretion of zalcitabine. This represents an increase in exposure to zalcitabine of approximately 50% and 36% with concomitant administration of probenecid and cimetidine, respectively. Patients receiving these drugs in combination with zalcitabine should be monitored for signs of toxicity and the dose of zalcitabine reduced if warranted.

Absorption of zalcitabine is moderately reduced (approximately 25%) when coadministered with magnesium/aluminum containing products. The clinical significance of this reduction is not known, hence zalcitabine is not recommended to be ingested simultaneously with magnesium/aluminum containing antacids. Bioavailability is mildly reduced (approximately 10%) when zalcitabine and metoclopramide are coadministered.

Administration of single doses of 1.5 mg zalcitabine during loperamide treatment (4 mg, 16 hours before zalcitabine; 2 mg, 10 and 4 hours before zalcitabine; and 2 mg, 2 hours after zalcitabine) to 12 HIV-positive patients with diarrhea resulted in no significant pharmacokinetic interaction between zalcitabine and loperamide.

Information for the Patient: Zalcitabine is not a cure for HIV infection. Illnesses associated with advanced HIV infection including opportunistic infections may still happen and zalcitabine has not been shown to reduce the incidence or frequency of such illnesses. Since it is frequently difficult to determine whether symptoms are a result of drug effect or underlying disease manifestation, all changes in your condition should be reported to your physician. The use of zalcitabine or other antiretroviral drugs do not preclude the ongoing need to maintain practices designed to prevent transmission of HIV.

The major toxicity of zalcitabine is peripheral neuropathy. Pancreatitis is another serious and potentially life-threatening toxicity that has been reported in 1.1% of patients treated with zalcitabine alone. Liver disturbances occur rarely, particularly in patients with a history of liver illness.

Symptoms of peripheral neuropathy include tingling, burning, pain or numbness in the hands or feet. Symptoms of pancreatitis include abdominal pain, and nausea and vomiting. Liver disturbances may not result in any symptoms, but can be recognized by your doctor through regular blood tests. All symptoms should be promptly reported to your physician. Since the development of peripheral neuropathy appears to be dose-related to zalcitabine, you should follow your physician’s instructions regarding the precribed dose.

The long-term effects of zalcitabine in combination with zidovudine are presently unknown.

If you are a female of child-bearing age, you should use effective contraception while using zalcitabine.

Adverse Reactions: The major toxicities of zalcitabine are peripheral neuropathy and, less frequently, pancreatitis (see Warnings).

The following data on adverse reactions are based primarily on the administration of zalcitabine at the recommended dose, as either monotherapy or in combination with zidovudine, to patients who are intolerant of or who have failed zidovudine and in patients with AIDS or advanced ARC (CD4 cell count 200 cells/mm.

These tables are followed by 2 lists of additional clinical adverse events which are possibly or probably related to study drug: a listing of events that occurred in the above trials at a frequency of
One patient with advanced HIV disease in Protocol N3447/ACTG 106 died of refractory acidosis, mild pancreatitis, hepatomegaly with steatosis, and an unexplained neurological syndrome. The investigator assessed this event as remotely related to zidovudine and/or the combination of zalcitabine and zidovudine. The occurrence of clinical adverse events at each dosage combination of zalcitabine and zidovudine did not vary significantly.

Other Adverse Events: Controlled Clinical Trials: Clinical adverse events considered possibly or probably related to study drug which occurred in

Body as a Whole: chest pain/tightness (1.7%), chills (1.0%); asthenia, dry eyes/mouth, general debilitation, stomach/abdominal cramps, hot/cold liquid intolerance, difficulty moving, pain (facial, flank, pelvic/groin, epigastric, extremities and/or generalized), infection (sepsis [H. influenza], herpes, septicemia), cutaneous/allergic reaction.
Cardiovascular: hypertension, cold hands/feet, tachycardia/heart racing, atrial fibrillation, cardiac dysrhythmias, ventricular ectopy, abnormal cardiac movement, subarachnoid hemorrhage, cardiomyopathy, thrombus.
Gastrointestinal: swallowing painful (1.2%); hemorrhoids, GI tract hemorrhage, anal/rectal pain, sore/inflamed or bleeding gums, ulcers (esophageal/rectal), dyspepsia, heartburn, pancreatitis, glossitis, loose stools, flatulence, abdominal bloating, abdomen enlarged, rectal mass, oral candidiasis, increased saliva, facial swelling, esophagitis, sore throat.
Hepatic: abnormal liver function tests (1.1%); hepatitis, jaundice, hepatocellular damage, hepatomegaly.
Lymph System: lymphadenopathy, lymphoma, unspecified hematologic toxicity, pancytopenia.
Metabolic/Nutrition: edema (unspecified and peripheral), polydipsia.
Musculoskeletal: musculoskeletal pain and/or weakness.
Nervous System: confusion, concentration impaired, convulsions/seizures, twitch, tremor, anxiety, amnesia/loss of memory, paranoid state, hypertonia, mood swings, psychotic episode, somnolence, stress reaction, hallucinations, neurologic function decreased, facial nerve palsy, vertigo, suicide attempt, decreased motivation/sexual desire.
Reproductive: testicular swelling, sore/swollen penis, vaginal ulcer/pain, vaginal/cervical disorder, vaginal itch, genital lesion.
Respiratory: dyspnea (1.7%); rales/rhonchi, sinus congestion/pain, acute nasopharyngitis, bacterial pneumonia, hemoptysis, chest congestion, shortness of breath, wheezing, dry nasal mucosa.
Skin/Mucous Membranes: dermatitis, exfoliative dermatitis, urticaria, cellulitis, impetigo, alopecia, cold sore, skin disorder, night sweats/chills, excessive sweating, lip blister, skin lesion, onychomycosis, carbuncle/furuncle, rash, epistaxis, skin ulcer, nail disorder, fissure (skin), dry skin, finger inflammation.
Special Senses/Vision: eye (pain, irritation, inflammation, hemorrhage), xerophthalmia, dry eyes, photophobia, vision (decrease, loss, blurred), tears increased, yellow sclera, redness of eyes, conjunctivitis, retinitis, ear pain, tinnitus, hearing loss, fluid in ears, taste perversion or decrease, smell dysfunction.
Urinary System: dysuria, urination (frequency), nocturia, abnormal renal function, glycosuria, bladder pain, renal cyst.
Other Adverse Events: Expanded Access Safety Study: Additional clinical adverse events at least possibly related to zalcitabine reported from 4 030 patients treated with either 0.375 mg or 0.750 mg q8h zalcitabine in expanded-access safety study (Protocol N3544), but not reported in the above controlled clinical trials are listed below by body system:

Body as a Whole: cachexia, rigors, influenza syndrome, sarcoma.
Cardiovascular: palpitation, cardiac failure, arrhythmia, syncope.
Gastrointestinal: eructation, left quadrant pain, colitis pseudomembranous, hairy leukoplakia, gastritis, salivary gland enlargement.
Hematologic: purpura.
Hepatic: cholecystitis.
Metabolic/Nutritional: anemia (0.7%); diabetes mellitus, hot flushes, aplastic anemia, hemolytic anemia.
Musculoskeletal: myositis, arthrosis, bursitis olecranon.
Nervous: neuritis (0.3%), nervousness (0.2%), agitation, depersonalization, neuralgia, ataxia, hyperkinesia, emotional lability, thinking abnormal, abnormal coordination, migraine, stupor, paralysis, speech disorder/dysphonia, euphoria, delirium.
Reproductive: impotence.
Skin/Mucous Membranes: flushing, infection, bullous eruption, acne, photosensitivity reaction, moniliasis.
Special Senses/Vision: ear blockage, parosmia, burning eyes, eye itching.
Urinary System: urinary retention, hyperuricemia, polyuria, renal calculus, gout, toxic nephropathy, acute renal failure, albuminuria.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Acute Overdosage: There is little experience with acute zalcitabine overdosage and the sequelae are unknown. There is no known antidote for zalcitabine overdosage. It is not known whether zalcitabine is dialyzable by peritoneal dialysis or hemodialysis.

Inadvertent pediatric overdoses have occurred with doses up to 1.5 mg/kg zalcitabine. The children had prompt gastric lavage and treatment with activated charcoal and had no sequelae. Mixed overdoses including zalcitabine and other drugs have led to drowsiness and vomiting (with zalcitabine or placebo, zidovudine and cotrimoxazole), or increased GGT (with 18.75 mg zalcitabine with zidovudine and lormetazam) or increased creatinine phosphokinase (with zalcitabine or placebo, zidovudine, fluconazole, dapsone and wine).

Chronic Overdosage: In an initial dose-finding study in which zalcitabine was administered at doses 25 times (0.25 mg/kg q8h) the currently recommended dose, 1 patient discontinued zalcitabine after one and one-half weeks of treatment subsequent to the development of a rash and fever.

In the early Phase I studies, all patients receiving zalcitabine at approximately 6 times the current total daily recommended dose experienced peripheral neuropathy by week 10. Eighty percent of patients who received approximately 2 times the current total daily recommended dose experienced peripheral neuropathy by week 12.

Dosage And Administration: The daily recommended monotherapy regimen is: one 0.75 mg tablet orally, administered every 8 hours, (2.25 mg zalcitabine total daily dose).

The daily recommended combination regimen is: one 0.75 mg tablet orally, administered concomitantly with 200 mg of zidovudine every 8 hours, (2.25 mg zalcitabine total daily dose and 600 mg zidovudine total daily dose).

Based on preliminary data, the following zalcitabine dose reductions are recommended for patients with impaired renal clearance: 0.75 mg zalcitabine every 12 hours (creatinine clearance of 10 to 40 mL/min); or 0.75 mg zalcitabine every 24 hours.

Monitoring of Patients: Periodic complete blood counts and clinical chemistry tests should be performed. Serum amylase levels should be monitored in those individuals who have a history of elevated amylase, pancreatitis, ethanol abuse, who are on parenteral nutrition or who are otherwise at high risk of pancreatitis. Careful monitoring for signs or symptoms suggestive of peripheral neuropathy is recommended, particularly in individuals with a low CD4 cell count or who are at a greater risk of developing peripheral neuropathy on therapy (see Warnings). All patients, particularly those at high risk, should be watched carefully for signs and symptoms of liver toxicity (see Warnings).

Dose Adjustment for Monotherapy with Zalcitabine and Combination Therapy with Zalcitabine and Zidovudine: For toxicities in patients receiving monotherapy which are likely to be associated with zalcitabine (e.g., peripheral neuropathy, severe oral ulcers) zalcitabine should be interrupted or dose reduced. For severe toxicities or those persisting after dose reduction, zalcitabine should be interrupted.

For recipients of combination therapy with zalcitabine and zidovudine, dose adjustments for either drug should be based on the known toxicity profile of the individual drugs. For toxicities more likely to be associated with zalcitabine (e.g., peripheral neuropathy, severe oral ulcers) zalcitabine should be interrupted or the dose reduced (see Warnings and Precautions).

For patients experiencing toxicities more likely to be associated with zidovudine (e.g., anemia, granulocytopenia), zidovudine should be interrupted or the dose reduced first.

For any interruption of zalcitabine, and especially if zalcitabine is permanently discontinued, the zidovudine dosage schedule should be adjusted from 200 mg q8h to 100 mg q4h as recommended in the product monograph for zidovudine.

For severe toxicities, toxicities in which the causative drug is unclear, or those persisting after dose interruption or reduction of one drug, the other drug should also be interrupted or the dose reduced. Physicians should refer to the product monograph for zidovudine for a description of known zidovudine-associated adverse reactions.

Patients developing moderate discomfort with signs or symptoms of peripheral neuropathy (e.g., numbness, tingling, hypoaesthesias, burning or shooting pains of the lower or upper extremities, or loss of vibratory sense or ankle reflex) should stop zalcitabine, especially if these symptoms are bilateral and progress for >72 hours. Zalcitabine-associated peripheral neuropathy may continue to worsen despite interruption of zalcitabine. Zalcitabine should be re-introduced (at 50% dose -0.375 mg q8h) only if all findings related to peripheral neuropathy have improved to mild symptoms. Zalcitabine should be permanently discontinued when patients experience severe discomfort related to peripheral neuropathy or moderate discomfort progressing for ³1 week.

If other moderate to severe clinical adverse reactions or laboratory abnormalities (such as increased liver function tests) occur, then zalcitabine in those patients receiving monotherapy, or both zalcitabine and zidovudine should be interrupted until the adverse reactions abate. Zalcitabine or zidovudine monotherapy or zalcitabine and zidovudine combination therapy should then be carefully reintroduced at lower doses if appropriate. If adverse reactions recur at the reduced dose, therapy should be discontinued. The minimum effective dose of zalcitabine in combination with zidovudine for the treatment of adult patients with advanced HIV infection has not been established.

In patients with poor bone marrow reserve, particularly those patients with advanced symptomatic HIV disease, frequent monitoring of hematologic indices is recommended to detect serious anemia or granulocytopenia. Zidovudine-related toxicities such as significant anemia (hemoglobin of 25% of baseline) and/or granulocytopenia (granulocyte count of 50% from baseline) may require a treatment interruption of zalcitabine and zidovudine until evidence of marrow recovery is observed. For less severe anemia or granulocytopenia, a reduction in daily dose of zidovudine in those patients receiving combination therapy may be adequate. In patients who experience hematologic toxicity, reduction in hemoglobin may occur as early as 2 to 4 weeks after initiation of therapy, and granulocytopenia usually occurs after 6 to 8 weeks of therapy. In patients who develop significant anemia, dose modification does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose modification, gradual increases in dose may be appropriate depending on hematologic indices and patient tolerance. For more details refer to the product monograph for zidovudine.

Availability And Storage: 0.375 mg: Each oval, beige, film-coated tablet, with Hivid 0.375 imprinted on one side and ROCHE on the other side, contains: zalcitabine 0.375 mg. Gluten-, parabens-, sucrose-, sulfites- and tartrazine-free. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and polysorbate 80 along with the following colorant system: brown, black, red and yellow iron oxide and titanium dioxide. Bottles of 100.

0.750 mg: Each oval, grey, film-coated tablet, with Hivid 0.750 imprinted on one side and ROCHE on the other side, contains: zalcitabine 0.750 mg. Gluten-, parabens-, sucrose-, sulfites- and tartrazine-free. Nonmedicinal ingredients: croscarmellose sodium, hydroxypropylmethylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and polysorbate 80 along with the following colorant system: black iron oxide and titanium dioxide. Bottles of 100.

Keep in a tightly closed container at 15 to 30°C. (Shown in Product Recognition Section)

HIVID® Roche Zalcitabine Antiretroviral Agent

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