a) A meta-analysis of 19 randomized clinical trials (n=2441 vinorelbine-treated patients; n=2050 control patients), comparing vinorelbine with other chemotherapeutic agents in the treatment of various malignancies, reported an incidence of cardiac events, cardiac deaths or toxic deaths of about 1% (1.19% [95% CI; 0.75; 1.67]). The risk of vinorelbine cardiac events was similar to other drugs (vindesine, fluorouracil, anthracyclines, gemcitabine) used in the same indications. The risk was higher in patients with pre-existing cardiac disease (Lapeyre-Mestre et al, 2004).

a) There have been rare reports of acute myocardial infarction following administration of vinorelbine (Prod Info vinorelbine tartrate IV injection, 2010; Zabernigg & Gattringer, 1996; Bergeron et al, 1995; Dubos et al, 1991).

a) Chest pain has been reported in 5% of cancer patients treated with vinorelbine. The majority of these patients had either a history of cardiovascular disease or a tumor within the chest (Prod Info vinorelbine tartrate IV injection, 2010).

a) There have been infrequent reports of acute dyspnea and severe bronchospasm following the administration of vinorelbine and other vinca alkaloids. This is most commonly seen when the vinca alkaloid was administered in combination with mitomycin. These effects may require treatment with oxygen, bronchodilators, and/or corticosteroids, especially in patients with preexisting pulmonary dysfunction. In addition, interstitial pulmonary changes and/or acute respiratory distress syndrome (ARDS) have been observed in patients receiving vinorelbine alone. In some cases, these events were fatal (Prod Info vinorelbine tartrate IV injection, 2010).
b) Pulmonary toxicity has been reported in less than 5% of patients receiving vinorelbine. Symptoms (bronchospasm, dyspnea, cough) are occasionally associated with interstitial infiltrates. In 1 case, complete resolution of respiratory symptoms occurred after 3 days of supportive care (ie, respirator, bronchodilators, steroids). Vinorelbine-related pulmonary toxicity may be an allergic reaction. Patients receiving high-dose vinorelbine therapy may be more susceptible to pulmonary toxicity (Raderer et al, 1996; Hohneker, 1994).
c) CASE REPORT: A 65-year-old man with a history of non-small cell lung cancer developed acute respiratory failure after receiving his initial dose of vinorelbine combined with mitomycin-C. Symptoms developed within an hour of completing the infusion and included severe dyspnea and wheezing. He did not initially respond to epinephrine or IV hydrocortisone. Rapid oxygen desaturation required immediate intubation and mechanical ventilation. An initial chest x-ray was consistent with pulmonary edema along with a massive right pleural effusion found on x-ray the following day. There was no evidence of cardiac involvement. Treatment included diuretics, dopamine and high-dose steroid therapy. By day 8, he was extubated and clinical signs and symptoms had improved (Uoshima et al, 2001).
d) CASE REPORT: Acute respiratory failure occurred 3 days after the initial infusion of vinorelbine (30 mg/m(2)) for the treatment of metastatic non-small-cell lung cancer in a 70-year-old man. His initial complaint of dyspnea was accompanied by diffuse, interstitial lung disease on chest x-ray. Despite aggressive treatment, the patient rapidly deteriorated and died. Whether vinorelbine and/or extensive malignancy caused the respiratory failure could not be determined (Kouroukis & Hings, 1997).

a) Acute pulmonary edema occurred in a woman treated with vinorelbine for metastatic breast cancer. The reaction occurred approximately 30 minutes after a 10-minute infusion of vinorelbine 30 mg/m(2) (52.5 mg). The patient improved markedly after two 40-mg doses of furosemide. Rechallenge with vinorelbine occurred more that 2 months later. Profound pulmonary edema developed approximately 45 minutes after completion of the infusion (Cattan & Oberg, 1999).

a) CASE REPORT: Acute bilateral pulmonary edema-related pneumopathy developed in a 45-year-old woman with metastatic non-small-cell lung cancer 4 days after receiving a total vinorelbine dose of 360 mg (240 mg/m(2)) instead of 36 mg. She was treated with diuretics and oxygen therapy. On day 6, she was presented to the bone marrow transplantation unit with fever (38.6 degrees C), tachycardia (130 bpm), dyspnea with a respiratory frequency at 35/mm and bilateral signs of acute lung disease. She also developed total paralytic ileus with severe abdominal distension, grade 1 peripheral neuropathy, grade 4 mucositis with fungi and herpes infection, severe cutaneous desquamation, grade 4 thrombocytopenia and grade 3 anemia. Following 24 days of supportive therapy, she was discharged from the bone marrow transplantation unit. She was in complete remission after 8 months (Lotz et al, 1997)

a) The most frequently reported mild to moderate peripheral neuropathies are loss of deep tendon reflexes, paresthesia and hypesthesia (Prod Info vinorelbine tartrate IV injection, 2010).
b) In patients with pre-existing sensory neuropathies, particularly those resulting from prior treatment with paclitaxel, vinorelbine has the potential to worsen the effects causing severe neurotoxicity. Neurotoxicity resulting from the combination of paclitaxel and vinorelbine appears to be very slowly reversible following discontinuation (Parimoo et al, 1996; Fazeny et al, 1996; Dittrich et al, 1994).
c) Neurotoxicity has been shown to increase with cumulative vinorelbine doses. The neurotoxic effects of vinorelbine are at least partially and in some cases completely reversible upon discontinuation of therapy (Pace et al, 1996; Besenval et al, 1989). In one study, 23 patients with advanced breast cancer were treated with vinorelbine 25 mg/week intravenously for 24 weeks. After 4 cycles of treatment, 47% of patients showed clinical signs and symptoms of mild neuropathy including absent ankle jerks and distal paresthesia. After 12 cycles, 47% of patients complained of dysesthesia in hands and feet and 73% showed deep tendon hyporeflexia. After 24 cycles, 50% of patients complained of dysesthesia in the lower limbs, 55% showed the absence of deep tendon reflexes, and 39% demonstrated hyporeflexia of ankle jerk (Pace et al, 1996).
d) By indirect comparison of studies, the neurotoxicity of vinorelbine appears less than that of other vinca alkaloids. With vincristine, a decrease in intensity/absence of osteotendinous reflexes, constipation, paresthesias, and paralytic ileus have been reported in 100%, 33% to 50%, 50%, and 3% to 12% of patients, respectively (Cvitkovic & Izzo, 1992; George et al, 1989). In one comparative trial, the incidence of neurotoxicity was significantly greater with a combination of vindesine plus cisplatin as compared to vinorelbine-cisplatin or vinorelbine alone in non-small cell lung cancer patients (Le Chevalier et al, 1992). However, clinical experience with vinorelbine is less than with other vinca alkaloids; further comparisons with other vinca alkaloids are required to confirm a significant advantage of the drug with regard to neurotoxicity.
e) Other frequently observed neurotoxic effects include constipation and paresthesias, which have occurred in 2% to 42% and 7% to 31% of patients, respectively, in most studies (George et al, 1989; Marty et al, 1992; Cvitkovic & Izzo, 1992; Canobbio et al, 1989). These effects have usually not been severe (grade 1 or 2). However, grade 3 or 4 constipation was reported in 8% of non-small cell lung cancer patients in one study (Depierre et al, 1991). A higher incidence of constipation has been reported in heavily pretreated ovarian cancer patients (grade 1 to 2 in 51% and grade 3 to 4 in 14% of patients) (George et al, 1989).
f) Decreased intensity or absence of deep tendon reflexes has occurred in 6% to 30% of cancer patients treated with intravenous vinorelbine (Cvitkovic & Izzo, 1992; Marty et al, 1992; Depierre et al, 1991).

a) Vinorelbine overdoses (10 times the recommended dose of 30 mg/m2) have caused paralytic ileus and paresis (Prod Info vinorelbine tartrate IV injection, 2010) .
b) CASE REPORT: A 45-year-old woman with metastatic non-small-cell lung cancer developed grade 1 peripheral neuropathy and transient confusion (lasting for 3 days) 6 days after receiving a total vinorelbine dose of 360 mg (240 mg/m(2)) instead of 36 mg. She also developed total paralytic ileus with severe abdominal distension, and grade 4 mucositis . Following 24 days of supportive therapy, she was discharged from the bone marrow transplantation unit. She was in complete remission after 8 months (Lotz et al, 1997).

a) Constipation (eg; grade 3 to 4), paralytic ileus, intestinal obstruction, necrosis, and/or perforation have been reported following vinorelbine therapy. Some of theses events have been fatal (Prod Info vinorelbine tartrate IV injection, 2010).
b) In single-agent use studies, constipation occurred in 29% of patients. Other gastrointestinal symptoms include nausea, vomiting and diarrhea. Mucositis has occurred with vinorelbine combined with cisplatin (Prod Info vinorelbine tartrate IV injection, 2010).

a) Vinorelbine overdoses (10 times the recommended dose of 30 mg/m2) have caused paralytic ileus, stomatitis and esophagitis (Prod Info vinorelbine tartrate IV injection, 2010).

a) Diarrhea has been observed in patients treated with vinorelbine as a single agent (Prod Info vinorelbine tartrate IV injection, 2010).
b) Oral vinorelbine has also been associated with acute diarrhea and severe nausea and vomiting (Budman, 1992a). Although the true incidence of these effects is unclear, they appear to be higher than with intravenous therapy (Feigal et al, 1993a; Budman, 1992a).
c) Grade 2 diarrhea has been observed in approximately 5% of patients treated with intravenous vinorelbine (Anon, 1992; Depierre et al, 1991).

a) CASE REPORT: A 45-year-old woman with metastatic non-small-cell lung cancer developed acute and severe diarrhea after receiving a total vinorelbine dose of 360 mg (240 mg/m(2)) instead of 36 mg (Lotz et al, 1997).

a) Severe mucositis was reported in 44% of cycles with a combination regimen of vinorelbine, leucovorin, 5-fluorouracil, and cisplatin in non-small cell lung cancer patients in one trial (Monnet et al, 1991). Several patients died due to sepsis during an episode of grade 4 mucositis and neutropenia. The authors speculated that vinorelbine may potentiate the mucosal toxicity of 5-fluorouracil, particularly when 5-fluorouracil is given in combination with leucovorin.

a) CASE REPORT: A 45-year-old woman with metastatic non-small-cell lung cancer developed grade 4 mucositis after receiving a total vinorelbine dose of 360 mg (240 mg/m(2)) instead of 36 mg (Lotz et al, 1997).

a) In single-use studies, mild to moderate nausea occurred in 34% of patients; severe nausea was observed in less than 2%. Vomiting was observed in 20% of patients receiving vinorelbine (Prod Info vinorelbine tartrate IV injection, 2010).
b) Oral vinorelbine has also been associated with acute diarrhea and severe nausea and vomiting (Budman, 1992a). Although the true incidence of these effects is unclear, they appear to be higher than with intravenous therapy (Feigal et al, 1993a; Budman, 1992a).
c) Severe nausea and vomiting are relatively infrequent during intravenous vinorelbine therapy. Grade 3 or 4 nausea and vomiting has been reported in 1% to 3% of cancer patients in most studies (Besenval et al, 1989; Marty et al, 1992; Cvitkovic & Izzo, 1992; Depierre et al, 1991). A higher incidence (8%) has occurred in heavily pretreated ovarian cancer patients (Besenval et al, 1989; George et al, 1989). Grade 1 to 2 nausea and vomiting has occurred in up to 50% of patients (Marty et al, 1992).

a) NEUTROPENIC ENTEROCOLITIS

a) Pancreatitis has been reported in postmarketing experience; incidence data are not available (Prod Info vinorelbine tartrate IV injection, 2010).
b) Two cases of vinorelbine-induced acute pancreatitis have been reported in women being treated for metastatic breast cancer. Both patients experienced nausea, vomiting, abdominal pain, and tenderness after either the first or second course of vinorelbine. Serum lipase levels were elevated in both patients (434 to 469 Units/L). Amylase levels were elevated (190 Units/L) in 1 patient and remained in the high-normal range in the other patient. One patient exhibited an elevated serum bilirubin and a 3-fold increase in transaminase levels. Both patients recovered with conservative symptomatic treatment within 3 to 11 days (Raderer et al, 1998; Tester et al, 1997).

a) Stomatitis has not been a major complication of single-agent IV vinorelbine therapy (grade 3 in up to 3% of patients, grade 1 to 2 in up to 7%) (Marty et al, 1992; Anon, 1992; Depierre et al, 1991; Canobbio et al, 1989).

a) Vinorelbine overdoses (10 times the recommended dose of 30 mg/m2) have caused stomatitis and esophagitis (Prod Info vinorelbine tartrate IV injection, 2010).

a) Constipation (eg; grade 3-4), paralytic ileus, intestinal obstruction, necrosis, and/or perforation have been reported following vinorelbine therapy. Some of theses events have been fatal (Prod Info vinorelbine tartrate IV injection, 2010).

a) Vinorelbine overdoses (10 times the recommended dose of 30 mg/m2) have caused paralytic ileus (Prod Info vinorelbine tartrate IV injection, 2010).
b) CASE REPORT: A 45-year-old woman with metastatic non-small-cell lung cancer developed total paralytic ileus with severe abdominal distension after receiving a total vinorelbine dose of 360 mg (240 mg/m(2)) instead of 36 mg (Lotz et al, 1997).

a) Elevations of serum total bilirubin and SGOT have been reported during intravenous vinorelbine therapy (Prod Info vinorelbine tartrate IV injection, 2010).

a) Hematologic toxicity of intravenous vinorelbine is not cumulative; neutrophil counts usually recover quickly allowing ongoing therapy. Myelosuppression is more likely to occur following second or third line therapy with vinorelbine (Galano et al, 2011).

a) Vinorelbine overdoses (10 times the recommended dose of 30 mg/m2) have caused severe bone marrow aplasia, sepsis, and death (Prod Info vinorelbine tartrate IV injection, 2010).
b) CASE REPORT: A 45-year-old woman with metastatic non-small-cell lung cancer developed fever and acute and severe diarrhea after receiving a total vinorelbine dose of 360 mg (240 mg/m(2)) instead of 36 mg. On day 1, plasmapheresis was performed to reduce the serum concentration of vinorelbine. She also developed severe thrombocytopenia requiring platelet transfusions and grade 3 anemia on day 3. The next day, she was admitted to the ICU and was treated with diuretics and oxygen therapy for acute bilateral pulmonary edema. In addition, she was treated with broad spectrum antibiotics and G-CSF therapy for grade 4 neutropenia and pulmonary sepsis. On day 6, she was presented to the bone marrow transplantation unit with fever (38.6 degrees C), tachycardia (130 bpm), dyspnea with a respiratory frequency at 35/mm and bilateral signs of acute lung disease, total paralytic ileus with severe abdominal distension, grade 1 peripheral neuropathy, grade 4 mucositis with fungi and herpes infection, and severe cutaneous desquamation. On day 10, she experienced transient confusion that lasted for 3 days. Neutropenia resolved after 16 days of supportive therapy. On day 24, she was discharged from the bone marrow transplantation unit. She was in complete remission after 8 months (Lotz et al, 1997).

a) Anemia occurs less frequently than neutropenia during vinorelbine therapy (Prod Info vinorelbine tartrate IV injection, 2010; Cvitkovic & Izzo, 1992; Marty et al, 1992; Depierre et al, 1991; Besenval et al, 1989). Grade 3 or 4 anemia in patients receiving weekly intravenous vinorelbine was reported in approximately 2% of cycles in phase II studies (n=1789 cycles) (Cvitkovic & Izzo, 1992). However, in pretreated ovarian cancer patients, the incidence of grade 3 to 4 anemia was relatively high (19%) in one study (George et al, 1989).
b) Grade 1 or 2 anemia has occurred in over 50% of patients in some studies (Marty et al, 1992; Canobbio et al, 1989).

a) A 45-year-old woman with metastatic non-small-cell lung cancer developed grade 3 anemia 3 days after receiving a total vinorelbine dose of 360 mg (240 mg/m(2)) instead of 36 mg (Lotz et al, 1997).

a) Granulocytopenia is the most frequent toxic effect of vinorelbine, and is dose-limiting (Prod Info vinorelbine tartrate IV injection, 2010; Cvitkovic & Izzo, 1992; Anon, 1992; Sorensen, 1992; Marty et al, 1992). Grade 3 to 4 neutropenia has been observed in 14% to 52% of cancer patients treated with weekly intravenous vinorelbine. Nadirs occur 7 to 10 days after the dose. It is reversible, with a usual duration of 7 to 14 days (mean, 9 days for grade 4), and is not cumulative (Prod Info vinorelbine tartrate IV injection, 2010; Marty et al, 1992; Cvitkovic & Izzo, 1992; Anon, 1992; George et al, 1989; Canobbio et al, 1989; Besenval et al, 1989). However, dose adjustments and/or delay of therapy have been required in up to 70% of patients and 20% to 40% of weekly cycles (Cvitkovic & Izzo, 1992); treatment courses have been delayed for 2 weeks or more due to prolonged neutropenia in some patients (Canobbio et al, 1989). Fever associated with neutropenia has been reported in less than 10% of patients (Marty et al, 1992).
b) Severe neutropenia has been more frequent with combination regimens in non-small cell lung cancer and breast cancer (Feigal et al, 1993a; Marty et al, 1992). In one study, grade 3 to 4 neutropenia occurred in 52%, 78%, and 47% of previously untreated non-small cell lung cancer patients during therapy with vinorelbine alone, vinorelbine plus cisplatin, and vindesine plus cisplatin, respectively (Le Chevalier et al, 1992).
c) Oral vinorelbine is also associated with neutropenia (Cvitkovic & Izzo, 1992; Budman, 1992a). Grade 3 to 4 neutropenia occurred in 32% of breast cancer patients treated with 50 to 160 mg weekly in one small study (Favre et al, 1989).
d) The incidence of severe neutropenia with vinorelbine appears greater than with vinblastine or vindesine. However, recovery times are shorter with vinorelbine; for grade 4 neutropenia, mean recovery times of 9 days have been reported with vinorelbine compared to a period of 14 to 21 days with vinblastine and vindesine (Cvitkovic & Izzo, 1992).

a) CASE REPORT: A 45-year-old woman with metastatic non-small-cell lung cancer developed grade 4 neutropenia after receiving a total vinorelbine dose of 360 mg (240 mg/m(2)) instead of 36 mg. Neutropenia resolved after 16 days of supportive therapy. On day 24, she was discharged from the bone marrow transplantation unit. She was in complete remission after 8 months (Lotz et al, 1997).

a) Thrombocytopenia is rare during intravenous vinorelbine therapy. The manufacturer reports an incidence of 1% for grade 3 or 4 thrombocytopenia (Prod Info vinorelbine tartrate IV injection, 2010). In phase II studies with heavily pretreated cancer patients, the incidence of grade 3 to 4 thrombocytopenia was only 1.2% of the total number of cycles administered (Cvitkovic & Izzo, 1992).
b) In studies with advanced breast cancer patients, grade 1 to 2 thrombocytopenia was reported in 4% or less of patients. The incidence of grade 3 to 4 thrombocytopenia was 1% when vinorelbine was used as second-line therapy, and 0% when used as first-line therapy (Marty et al, 1992).

a) CASE REPORT: A 45-year-old woman with metastatic non-small-cell lung cancer developed severe grade 4 thrombocytopenia requiring platelet transfusions 3 days after receiving a total vinorelbine dose of 360 mg (240 mg/m(2)) instead of 36 mg (Lotz et al, 1997).

a) The severity of skin or venous reactions has been greater with continuous intravenous infusion of vinorelbine, with grade 3 to 4 reactions occurring in 16% of patients in phase II studies (Cvitkovic & Izzo, 1992).
b) Supravenous hyperpigmentation at the injection site of vinorelbine 25 mg/m(2) has been reported in a 60-year-old man. The patient developed a streaky dark-brown hyperpigmentation 3 days after the third IV infusion of once weekly vinorelbine therapy. Further injections increased the reaction (Cecchi et al, 1994).
c) Grade 3 or 4 local cutaneous or venous reactions (eg, pain on injection, venous pain, and thrombophlebitis) to intravenous vinorelbine have occurred in 5% to 10% of patients receiving short infusions (20 minutes) (Anon, 1992; Depierre et al, 1991; George et al, 1989; Besenval et al, 1989). The incidence of less severe reactions (grade 1 to 2) is 10% to 33% (Anon, 1992; Depierre et al, 1991; George et al, 1989; Canobbio et al, 1989). However, local reactions to infusion were not reported at all in some studies, and their incidence was unclear in other; the true incidence of these complications requires further study.
d) Local inflammatory reactions have been reported for several days after implantation of vinorelbine polymeric implants. These reactions were effectively treated with nonsteroidal antiinflammatory agents (Fournier et al, 1991).

a) CASE REPORT: A 45-year-old woman with metastatic non-small-cell lung cancer developed severe cutaneous desquamation after receiving a total vinorelbine dose of 360 mg (240 mg/m(2)) instead of 36 mg (Lotz et al, 1997).

a) Hand-Foot Syndrome (HFS), also known as Palmar-plantar erythrodysesthesia, has been associated with long infusions of vinorelbine. In one study, 7% of patients developed HFS following a 96-hour continuous infusion. Patients received an initial intravenous bolus dose of 8 mg/m(2) followed by a 96-hour continuous infusion (7 to 14 mg/m(2)/day) repeated every 4 weeks. HFS is characterized by paresthesia, erythema, and pain in the palms and soles. In severely affected patients, skin desquamation in those areas may occur. HFS may be dose related, occurring more frequently at doses above 10 mg/m(2)/day. HFS improves with discontinuation of therapy and skin regenerates normally. Premedication with steroids may prevent HFS (Hoff et al, 1998).

a) Grade 1 to 2 alopecia has been reported in up to 34% of cancer patients treated with intravenous vinorelbine (Prod Info vinorelbine tartrate IV injection, 2010). However, grade 3 to 4 alopecia is less common (4% to 12% of patients) (Anon, 1992; Marty et al, 1992; Cvitkovic & Izzo, 1992; Depierre et al, 1991; George et al, 1989).

a) Rash has been reported with vinorelbine therapy (Prod Info vinorelbine tartrate IV injection, 2010).

a) Myalgia, arthralgia, and muscle weakness have been reported with intravenous vinorelbine, although the true incidence of these complications is unclear (Prod Info vinorelbine tartrate IV injection, 2010; Besenval et al, 1989; Canobbio et al, 1989). Grade 1 myalgia was described in 16% of patients in one study (Canobbio et al, 1989). These complications are considered secondary to the neurotoxicity of vinorelbine.

a) The reports an incidence of jaw pain of less than 5% in patients receiving vinorelbine (Prod Info vinorelbine tartrate IV injection, 2010).
b) Myalgia, muscle weakness, and jaw pain, (also considered neurotoxic effects), have occurred with vinorelbine although their true incidence is unclear (Depierre et al, 1991; Canobbio et al, 1991; Besenval et al, 1989; Canobbio et al, 1989). Grade 3 jaw pain occurred in 1.3% of non-small cell lung cancer patients treated with intravenous vinorelbine in one study (Depierre et al, 1991).

a) The syndrome of inappropriate antidiuretic hormone (SIADH) has been reported in less than 1% of patients receiving vinorelbine (Prod Info vinorelbine tartrate IV injection, 2010).
b) CASE REPORT: A 50-year-old woman receiving vinorelbine for mediastinal recurrence of breast cancer developed the syndrome of inappropriate antidiuretic hormone (SIADH) after 2 courses of chemotherapy. On presentation for the third cycle, serum chemistry measurements showed a reduced sodium concentration of 111 mEq/L. Urinary sodium was 58 mEq/L with an osmolality of 761 mOsm/kg. Failing to respond to conservative treatment, an infusion of 3% sodium chloride was started at a rate of approximately 1 mEq/L/hour with furosemide injections. Demeclocycline 300 mg twice daily to continue for the duration of vinorelbine therapy was prescribed and SIADH did not recur (Garrett & Simpson, 1998).

a) Allergic-type reactions to intravenous vinorelbine have been reported occasionally (2% of patients) (Depierre et al, 1991; Anon, 1992), although details of these reactions were not provided.

a) Embryotoxicity and fetotoxicity were reported in mice and rabbits at doses of 9 mg/m(2) and 5.5 mg/m(2) (one third and one sixth the human dose), respectively. Fetal weight and reduced ossification was delayed at non-maternal doses (Prod Info vinorelbine tartrate IV injection, 2010).

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS